Journal of Neuroinflammation(2024) 21:188
Zou et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-024-03181-w

Open Access

REVIEW

Neuroimmune modulation in liver
pathophysiology
Ju Zou1,2,3, Jie Li1,2,3, Xiaoxu Wang1,2,3, Daolin Tang4 and Ruochan Chen1,2,3*

Abstract
The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both thecentral and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vitalfor maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines,
inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate thiscomplex communication. They establish feedback loops among diverse immune cell populations and the central,
peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we
provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We
further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting
their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches
targeting neuroimmune interactions and present prospects for future research in this area.
Keywords Liver disease, Autonomic nervous system, Sympathetic nervous system, Parasympathetic nervous system,
Neuroimmune system
Introduction
The nervous and immune systems are crucial for survival.
Traditionally, these systems were believed to function
independently; however, accumulating scientific evidence
suggests an active and beneficial dialogue between them[1]. The liver, innervated by autonomic and sensory fibers of the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS), plays a pivotal role

*Correspondence:
Ruochan Chen
405031@csu.edu.cn
1
Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South
University, Changsha 410008, Hunan, China
2
Department of Infectious Diseases, Xiangya Hospital, Central South
University, Changsha 410008, Hunan, China
3
National Clinical Research Center for Geriatric Disorders, Xiangya
Hospital, Central South University, Changsha 410008, Hunan, China
4
Department of Surgery, UT Southwestern Medical Center, Dallas, TX,
USA

in various life-sustaining functions, including digestion, coagulation, synthesis, metabolism, detoxification,and immune defense [2, 3]. Liver injury, responsible forapproximately 2 million deaths worldwide annually, canresult from toxins, metabolic disorders, infections, andgenetic diseases [4]. The initial presentation of mostchronic and many non-fulminant acute liver diseases isoften asymptomatic or involves nonspecific signs andsymptoms, such as fatigue, anorexia, and weight loss [5–7]. It is only when the liver capsule or intrahepatic bile
duct is involved in inflammation, such as in Fitz-HughCurtis syndrome [8] and hepatolithiasis, [9] that patientscomplain of right upper quadrant pain. Liver transplantation leads to effective liver denervation, which may
contribute to higher rates of obesity, dyslipidemia, anddiabetes in liver transplant recipients [10–13]. Theseobservations suggest a strong communication between
the liver (including the liver capsule, hilar region, portal
region, and liver parenchyma) and the nervous system.

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Zou et al. Journal of Neuroinflammation(2024) 21:188

Although the role of the hepatic nervous system in liver
homeostasis is increasingly appreciated, much remains
unknown about the specific mechanisms by which
hepatic nerves influence and are influenced by liver diseases. Both human and rodent livers are innervated by
the autonomic nervous system (ANS). While the humanliver is innervated by the SNS and PSNS, the rodent liver
may be innervated only by the former [14]. The liver possesses a finely tuned cellular immune system, including
innate immune cells such as Kupffer cells (KCs), monocyte-derived macrophages, dendritic cells (DCs), natural killer (NK) cells, natural killer T cells, and adaptive
immune cells, such as T and B cells. Disruption of thehepatic immune system can cause autoimmune hepatitis,
steatohepatitis, cirrhosis, and liver cancer [15]. Although
the positional relationships between the nerves andimmune cells in the liver are unclear, the role of neuroimmunology in liver diseases has been explored throughsurgical and genetic techniques. Given the fundamental
connection between the nervous system and liver, understanding the role of neuroimmune innervation in liver
dysfunction holds promise for developing novel therapeutic approaches for liver diseases.
In this concise review, we provide a brief descriptionof the structure and composition of the hepatic neuraland immune systems. Subsequently, we introduce themolecular mechanisms and pathways that mediate neuroimmune communications and discuss their significance in liver ailments. Lastly, we summarize the current
clinical implications of therapeutic strategies targeting
neuroimmune interactions and propose future research
directions.

Hepatic nervous and immune systems
Hepatic neuroanatomy

The neural circuitry connecting the nervous system
and liver is intricate. The centrifugal neural circuits are
divided into the central nervous system (CNS), which
includes the brain and spinal cord, and the peripheral
nervous system (PNS), comprising somatic and autonomic nerves [16]. The somatic nerves, originating fromthe CNS, regulate skeletal muscles and elicit voluntary
movements [17]. The ANS consists of the SNS, PSNS,
and enteric nervous system (Fig. 1) [18]. The afferent
neural circuits are broadly divided into afferent vagus andspinal sensory nerves [19]. The cell bodies of the afferent
vagus nerves are situated in two nodose ganglia on eitherside of the neck, with the left and right vagus nerves
innervating visceral organs asymmetrically [20].
Autonomic nerves, both afferent and efferent, innervate various parts of the liver, including the portal
vein, hepatic artery, bile ducts, and liver hilum [21].

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The anterior plexus, originating from the left portionof the celiac plexus and the right abdominal branch of
the vagus, forms a network of nerves surrounding thehepatic artery. The posterior plexus, derived from theright portion of the celiac plexus, surrounds the portal vein, occasionally extending innervations accompanying the hepatic vein (Fig. 2A). The distribution of
nerves within the liver is highly species-specific, withmost species exhibiting innervation of the portal tract[13]. For instance, while the human liver exhibits both
intra-acinar and portal tract innervation, mice andrats primarily display portal tract innervation (Fig. 2B)[14]. The distribution of nerves within the liver in various species, such as rats, rabbits, monkeys, guinea pigs,
pigeons, quail, golden hamsters, and turtles, has beenthoroughly reviewed in previous studies [13].
Hepatic immune system

The mammalian liver is a multifaceted organ withdiverse cell types that perform numerous physiological functions, [22–24] including digestion, synthesis,
metabolism, and detoxification. Additionally, the liver
plays a vital role in immune processes, such as antiinfection, maintaining autoimmune stability, and supporting antitumor activities (Fig. 3A) [25–27]. One of
the liver’s unique immunological advantages stems
from its parenchymal and nonparenchymal cells, which
actively contribute to immunoregulation and the maintenance of overall homeostasis. As a fundamental
immune organ, the liver receives blood directly throughthe portal vein, which drains not only the peritoneum
but also the gastrointestinal (GI) tract, pancreas, andspleen [28]. This direct blood supply bypasses classic
immune surveillance sites such as lymph nodes [29].
Notably, the liver is more exposed to microorganisms
and endotoxins than other organs, given its distinctive anatomical location and unique blood composition (mainly derived from the portal vein and enrichedwith antigens from the GI tract) [30]. Consequently,
the liver typically maintains a tolerogenic immune
state to prevent unnecessary immune activation andexcessive autoimmune responses [31, 32]. However,during acute and chronic infections, the liver transitions from a tolerant state to an active immune state,
constituting a crucial line of defense against invading
microorganisms [33–36]. Hepatic defenses depend on
a complex network of immune cells, including KCs,
DCs, neutrophils, NK cells, and B and T lymphocytes[37]. Furthermore, non-immune cells, such as hepatocytes, cholangiocytes, hepatic stellate cells (HSCs),
and liver sinusoidal endothelial cells play pivotal roles

Zou et al. Journal of Neuroinflammation(2024) 21:188

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Fig. 1 The classification of the nervous system and the summary of peripheral nervous system (PNS). A Classification of the nervous system. B
Summary of efferent pathways in the PNS. The autonomic nervous system is organized in three anatomical and biochemical distinct systems,
the sympathetic nervous system (SNS, in red), the parasympathetic nervous system (PNS, in blue) and the enteric nervous system (ENS,
Fig. 1D), respectively. C Summary of the afferent pathways in the PNS (in the liver and gut). D Schematic diagram of the ENS. The ENS is locatedwithin intestinal tissues and has a characteristic architecture. CNS central nervous system, ENS enteric nervous system, PNS peripheral nervous
system, PSNS parasympathetic nerve system, SNS sympathetic nerve system, III the third cranial nerve, VII the seventh cranial nerve, IX the ninth
cranial nerve, X the tenth cranial nerve

in recruiting proinflammatory immune cells and concurrently producing inflammatory cytokines, including acute-phase proteins, complement factors, and celladhesion molecules (Fig. 3B) [38–40].

Mechanisms of neuroimmune interactionin the liver
The interactions between neurons and immune cells are
intricate and multifaceted, necessitating a sophisticatedZou et al. Journal of Neuroinflammation(2024) 21:188

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Fig. 2 Hepatic neuroanatomy. A Origin and concomitant of hepatic plexus. The anterior plexus, originating from the left portion of the celiac
plexus and the right abdominal branch of the vagus, forms a network of nerves surrounding the hepatic artery. Meanwhile, the posterior plexus,
derived from the right portion of the celiac plexus, is located around the portal vein with occasional innervations accompanying the hepatic vein.
B Anatomy of the intrinsic sympathetic and parasympathetic nerve fibers. In all mammalian species, sympathetic and parasympathetic fibers
surround the portal are an humans and guinea pigs but not rats. sympathetic fibers course into liver sinusoids. C Innervation of the human liver.
Within the liver, nerves are found around the hepatic artery, portal vein, and bile ducts. Sympathetic nerves, but not parasympathetic nerves,
synapse on hepatocytes as well. LSEC liver sinusoids endothelial cell

Zou et al. Journal of Neuroinflammation(2024) 21:188

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Fig. 3 Hepatic immune system and functions. A Functions of the liver. The mammalian liveris a complex organ consisting of diverse cell types
that perform multiple physiologicalfunctions including digestion, detoxication, metabolism, biotransformation,and immune. B Hepatic immune
system. The liver’s immune defense mechanism primarily depends on a complex network of immune cells and non-immune cells, the latterof which play immune roles by recruiting proinflammatory immune cells and simultaneously producing inflammatory cytokines

Zou et al. Journal of Neuroinflammation(2024) 21:188

infrastructure to enable signal propagation between these
two systems. In the following sections, we delve into
the principal pathways through which the nervous andperipheral immune systems communicate and influenceeach other (Fig. 4A). Each pathway serves as a distinct
conduit for transmitting specific information, employing
unique mechanisms to convey messages.
Endocrine pathways

The endocrine system is a powerful tool at the brain’s
disposal, regulating many physiological processes. Hormones, controlled by the brain, are released into thebloodstream and transported to target tissues andimmune cells. This rapid and efficient pathway simultaneously delivers information to various organs and synchronizes physiological processes. At the center of this systemis the hypothalamus, which communicates extensively
with other brain regions and governs vital processes, suchas hunger, thirst, body temperature, circadian rhythm,
and sleep.
The hypothalamus regulates two primary endocrine
pathways: the hypothalamic–neurohypophyseal systemand the hypothalamic–hypophyseal portal system. In
the hypothalamic–neurohypophyseal system, hormones,
including oxytocin [41] and arginine-vasopressin (AVP),[42] are produced and secreted. Oxytocin suppresses
proinflammatory cytokines [43, 44] and promotes woundhealing, [45] while AVP exerts anti-inflammatory effects
during sepsis [46]. The activation of AVP-producing neurons by inflammatory cytokines indicates that this endocrine pathway can respond to changes in immune system
activity [47].
The hypothalamic–hypophyseal portal system secretes
hypothalamic hormones into the bloodstream to ultimately
reach the target organ, inducing the release of the final
effector hormone. There are five main axes, [1] including
the (1) hypothalamic–pituitary–adrenal axis; (2) hypothalamic–pituitary–thyroid axis; (3) hypothalamic–pituitary–
gonadal axis; (4) hypothalamic–pituitary–somatotropic

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axis; and (5) hypothalamic–pituitary–prolactin axis.
These endocrine pathways coordinate physiological anddevelopmental events that necessitate adjustments inimmune activity, thus influencing the immune response.
For instance, sex hormones play a role in the programmingof the immune system [48, 49]. Testosterone generally has
an immunosuppressive effect, whereas estrogen enhances
immune responses [50]. The immunoenhancing effects ofestrogens include promotion of neutrophil infiltration, elevation of macrophage phagocytic activity, enhancement of
DC antigen-presenting function, promotion of Th2 differentiation, and contributions from T-lymphocytes, B-lymphocytes, cytotoxic CD8 cells, NK cells, and ILC-2 cells[51–53]. Consequently, females exhibit increased antibody production [54, 55] and are less susceptible to viral
infections but more prone to autoimmune diseases [56,57]. Androgens suppress the immune response throughmechanisms such as influencing neutrophil maturationand function, decreasing TNF-α and IL-1β expression andsecretion in macrophages, negatively regulating B- andT-cell development, reducing toll-like receptor expression,and decreasing cytokine production [51, 58]. These mechanisms partly explain the increased susceptibility of males
to various parasitic, [59] bacterial, [60] and viral infections [61, 62]. Similarly, androgen-mediated suppressionof immune reactivity and inflammation lowers the threshold for cancer, making men more susceptible to cancer
than women [63]. Diseases such as primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) have a strong
female predominance, whereas primary sclerosing cholangitis (PSC) has a higher incidence in males with a more
severe course [64]. The strong association between sex andthe development and course of autoimmune liver diseases
could be partially explained by differences in sex hormones[65]. Another example is the hypothalamic–pituitary–thyroid axis, which boosts metabolic activity and is linked toimmune activation [66]. Thyroid hormones induce lymphocyte proliferation [67]. Consequently, the immune
response is suppressed by thyroidectomy, [68] and patients(See figure on next page.)
Fig. 4 Neuronal regulation of immune activation. A Outline. An overview of inter-regulation of the nervous system and the immune system.
B Endocrine pathways. The endocrine signals enable the synchronization of complex physiological processes and immune activity. C Neuronalefferent pathways. Noradrenaline (recognized by α-adrenergic and β-adrenergic receptors) is the primary neurotransmitter of the SNS,
while acetylcholine (ACh; recognized by nicotinic and muscarinic ACh receptors) is the primary PSNS neurotransmitter. Both of which can affectactivity of immune organs and immune cells. D Meningeal lymphatic vessels. The meningeal lymphatic system can impact both the central
and peripheral immune response by transporting immune cells and antigens from the brain to the peripheral immune system. ACTH
adrenocorticotropic hormone, ANS autonomic nervous system, Ach acetylcholine, AI Alzheimer’s disease, AVP arginine vasopressin, CNS central
nervous system, CCL21 C–C motif chemokine ligand 21, Epi epinephrine, FSH follicle-stimulating hormone, GH growth hormone, LH luteinizing
hormone, M-R muscarinic cholinergic receptor, MS multiple sclerosis, N1-R nicotinic cholinergic receptor type 1, NA norepinephrine, OXT oxytocin,
PVN paraventricular nucleus, PRL prolactin, PNS peripheral nervous system, PSNS parasympathetic nerve system, PROX1 prospero homeobox 1,
SON supraoptic nucleus, TSH thyroid stimulating hormone, VEGFR3 also known as “FLT4,” fms related receptor tyrosine kinase 4, α/β-R adrenergic
cholinergic receptor

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Fig. 4 (See legend on previous page.)(2024) 21:188

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Zou et al. Journal of Neuroinflammation(2024) 21:188

with hypothyroidism are more susceptible to infection [69,70]. Thus, endocrine signals synchronize complex physiological processes and immune activity (Fig. 4B).
Neuronal efferent pathways

The human CNS communicates rapidly and directlywith peripheral tissues through the PNS, comprising 12 cranial nerves, 31 spinal nerves, and the ANS[71]. The ANS regulates functions not under conscious control, such as blood pressure, heart rate, andGI motility and function. The SNS and PSNS have
opposing effects on various physiological processes;
the SNS regulates the “fight or flight” response, while
the PSNS regulates the “rest and digest” state. Manyorgans, including the bone marrow, lymphatic tissues
and organs, joints, blood vessels, lungs, GI tract, liver,kidneys, and spleen, are innervated by the ANS [17].
Noradrenaline, acting through α-adrenergic andβ-adrenergic receptors, is the primary neurotransmitter of the SNS, whereas acetylcholine (ACh), acting through nicotinic and muscarinic receptors, is theprimary neurotransmitter of the PSNS. Although both
systems can influence immune activity, immune organs
such as the bone marrow, thymus, lymph nodes, andspleen are predominantly innervated by the SNS [72].
Immune cells, such as NK cells, DCs, T cells, and macrophages, express receptors for neurotransmitters andneuropeptides secreted by the ANS [73, 74]. Notably,
immune cells themselves can also secrete various neuronal factors, [74–76] revealing an intricate interplay
between the nervous system and immunity (Fig. 4C).

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model of Alzheimer’s disease, disruptions in meningeal lymphatic vessels promoted meningeal amyloid-β
deposition and increased parenchymal amyloid-β
accumulation (Fig. 4D) [80]. Therefore, by transporting immune cells and antigens from the brain to theperiphery, the meningeal lymphatic system can impact
both central and peripheral immune responses.

Immune regulations of neuronal function
Cytokine pathways

The recognition of immune influences on the nervous system has become more evident, though it initially
lagged behind our understanding of how the nervous
system regulates the immune system. This delay was
primarily due to the recent discovery of the molecularmechanisms governing immune communication signals
and pathways, particularly cytokines [81]. Cytokines, primarily released by immune cells, notably T cells and myeloid cells, play a pivotal role in active immune responses[81]. Afferent fibers of the ANS can detect cytokines andtransmit this information to the brain, forming a "neural"communication pathway [82]. For instance, in adult mice,the intraperitoneal administration of tumor necrosis factor (TNF) or interleukin-1β significantly alters the action
potentials originating from the cervical vagus nerve [83].
Cytokines can also directly activate and sensitize neurons, leading to the generation of action potentials thatconvey information to the brain (Fig. 5) [84–87]. Underinflammatory conditions, cytokines may directly reachparenchymal brain centers via a “humoral” route, particularly when the blood–brain barrier (BBB) exhibits
increased permeability [88].

Meningeal lymphatic vessels

The brain can regulate immune responses by introducing brain-specific antigens to the peripheral immune
system. Immune cells continually monitor all tissues,
residing or patrolling within them to gather information about the tissue’s condition and potential threats.
These cells then travel through lymphatic vessels tothe lymph nodes, where they present antigens and trigger a relevant immune response [77]. Recent research
has identified dural lymphatic vessels that transport antigens and immune cells from the brain to thelymph nodes and express lymphatic endothelial markers, such as PROX1, CCL21, and VEGFR3 [78]. The
lymphatic system envelops the brain, facilitating thedrainage of excess fluid, proteins, and immune cells
from the brain tissue to peripheral lymph nodes [79].
In a mouse model of multiple sclerosis, the removalof this meningeal lymphatic system led to a reductionin CNS disease and a decrease in T cell inflammatory responses [79]. Similarly, in a transgenic mouse

Afferent neural inputs

Peripheral primary afferent neurons express receptors for
microbial constituents and inflammatory products, indicating their role as a hardwired neural connection thatsignals inflammation or infection from the periphery to
the CNS (Fig. 5). The sensory nervous system is a crucialcomponent of afferent neural circuits, transmitting signals from peripheral tissues to the brain and spinal cord[89]. Various pathogen-associated molecular patterns,
such as unmethylated cytosine and guanine and lipopolysaccharide (LPS), as well as danger-associated molecularpatterns including DNA, histones, HMGB1, adenosine
triphosphate, uric acid, and cytokines, can be detectedby sensory nerves [90]. In regions of infection or injury,
the activation of peripheral immune cells and the releaseof cytokines and other inflammatory molecules influence
sensory neurons, either triggering or altering signals sent
to the spinal cord and brain [91].

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Fig. 5 Immune regulation of neuronal function. The pathways in which immune influences on the nervous system consist of cytokines, afferent
neural inputs, and chemoreceptors (including osmoreceptors, ion receptors, and metabolic substance receptors). DAPMs damage-associatedmolecule patterns, GLUT2 glucose transporter 2, NKCC1 Na +-K+-2Cl− cotransporter, PKC protein kinase C, PAMPs pathogen-associated molecularpatterns, TRPV4 transient receptor potential vanilloid 4

Furthermore, sensory neurons in the liver play arole in detecting nutritional and absorptive hormones
known as incretins. One prominent incretin, glucagonlike peptide 1 (GLP-1), is sensed by afferent nerves in
the portal vein. Activation of GLP-1 receptors stimulates hepatic vagal afferent nerves, leading to changes
in pancreatic insulin release through efferent sympathetic nerve signals originating in the brain [92, 93].
Hepatic afferent fibers also express receptors for several
hormones secreted by the GI tract, including somatostatin, [94] leptin, [95] and cholecystokinin [96].
In addition to their primary function of transmitting
information to the brain, these neurons locally releaseneuropeptides. Sensory fibers have been extensively
studied for their ability to communicate with immune

cells, [97] particularly in barrier tissues, such as the skin,[98, 99] lungs, [100] and gut, [101, 102] where immune
cells are abundant. These sensory innervations directly
affect immune cell activity, providing protection against
endotoxemia [103] and sepsis [104]. Therefore, the sensory nervous system has both systemic and local effects
on immunity, conveying sensory inputs to the brain to
regulate the peripheral immune response and secreting
neuropeptides directly into the tissues [104].
Chemoreceptors

The liver serves as an ideal sensor for monitoring
osmolality, glucose concentration, and fatty acid levels due to its close connection with the GI tract. Following the absorption of macronutrients from the GI

Zou et al. Journal of Neuroinflammation(2024) 21:188

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tract, they travel through the portal vein to reach theliver. Within the liver, numerous chemoreceptors playa critical role in sensing ions and nutrients and subsequently transmit signals to the brain. Additionally, several chemoreceptors are multifacetedly correlated withimmune response or even neuro-immune communication. These chemoreceptors encompass osmoreceptors,
ion receptors, and receptors for various metabolic substances (Fig. 5) [14].

or hypochloremia, stemming from the loss of the hepatorenal reflex. Ions serve as critical neurotransmitters in
the neuroimmune network in various organs such as thebrain and kidneys. Calcium sensing via microglial UDPspecific type 6 purinergic (P2Y6) signaling pathways wasreported to promote microglia phagocytosis and shapeneuroimmune responses in epileptogenesis [112]. However, the role of ions in liver neuroimmune communication needs further investigation.

Osmoreceptors

Metabolic sensing

While the brainstem is responsible for detecting disturbances in osmolarity, the liver harbors peripheral osmoreceptors that are quite effective at detecting changes inblood osmolality. This is particularly relevant because
the liver can detect changes in water intake before thesechanges affect systemic blood osmolality [105]. Neurons adjacent to hepatic blood vessels are responsible fordetecting and responding to shifts in osmolality within
the liver, [105] relying on osmotically-activated ionchannels such as transient receptor potential vanilloid
4 (TRPV4) [105]. TRP channels potentiate the inflammatory response following hepatocellular injury by controlling the functions of Kupffer cells, monocytes, andneutrophils, including cytokine and chemokine production, response to chemokines, adhesion, and migration from the bloodstream to injured hepatic sites [106].
Impaired osmoregulation of vasopressin also occurs in
the acute phase of severe sepsis, resulting from a depolarization of osmoreceptors, which leads to sick behaviors caused by brain-immune crosstalk dysfunction in
response to stress, indicating a crucial role of osmoreceptors in neuro-immune communication [107]. Activationof hepatic osmoreceptors is linked to various physiological and clinical parameters. For instance, water consumption has been associated with outcomes such as weight
loss, [108] hepatic denervation, [109] and orthostatic andpostprandial hypotension [105].

Hepatic afferent fibers establish a negative feedback loop
involving feeding behavior and metabolite level alterations. Peripheral glucose sensors are distributed in various locations, including the taste buds, intestines, carotid
bodies, and liver [113–115]. Emerging evidence points tothe wall of the portal vein as a probable site for glucose
sensing [116]. In the liver, GLUT2 serves as a hepatoportal glucose sensor with a role in hyperglycemia detection[35]. A Glut2–/– knockout mouse model demonstrated afailed hypoglycemic response to portal glucose infusion[35]. However, the exact molecular pathway responsible
for hepatic lipid sensing remains undefined. One potential pathway involves the activation of protein kinase C(PKC) δ, θ, and ε [117]. Notably, lipid activation of PKCs
is not limited to the liver, as PKC-δ is activated during
lipid sensing in duodenal cells as well [118]. This pathway’s activation regulates glucose production through a
gut–brain–liver mechanism. A study by Seillet et al. elegantly demonstrated the interdependence of the neuroimmune-metabolic network in steady-state conditions
with respect to lipid metabolism [119]. The key findingis that intrinsic cellular rhythms acted in synergy withthe cyclic patterns of food intake to drive the productionof IL-22 and synchronize the protection of the intestinal epithelium through a vasoactive intestinal peptide(VIP)-vasoactive intestinal peptide receptor 2 (VIPR2)
pathway in group 3 innate lymphoid cells (ILC3s). IL-22
released by the ILC3s improves insulin sensitivity andcan regulate lipid metabolism in the liver and adipose
tissue [120]. The combined input of afferent signals fromthe gut and liver may trigger hypothalamic activity during food intake [121]. Ongoing research should further
investigate the potential intersections of lipid- or othermetabolite-induced signaling in the brain, liver, gut, andother organs.

Ion sensation

The liver possesses receptors that monitor fluid homeostasis by detecting key physiological ions in the portal blood system. Similar to osmoreception, the hepatic
nervous system identifies changes in ion concentrations
before they impact the entire system [110]. The liver
holds a distinct advantage in ion detection compared toother organs, given that the concentration of absorbed
substances in the portal vein is 4–5 times higher thanwhat is observed in the systemic blood [111]. Consequently, the liver serves as an ideal "predictor" of systemic
blood ion concentrations, allowing for the anticipationof abnormal fluid homeostasis. Patients with cirrhosis
commonly exhibit ion imbalances such as hyponatremia

Interaction between liver pathology
and neuroimmunity
The interplay between liver pathology and neuroimmune disorders is complex. Although the exact connection between nerves and immune cells within theliver remains elusive, the field of neuroimmunology has

Zou et al. Journal of Neuroinflammation(2024) 21:188

investigated liver diseases through surgical and genetic
techniques. Recent findings indicate that the nervous
system plays a pivotal role in the onset and progressionof various liver diseases. Liver diseases frequently coincide with dysfunction in both the CNS and PNS. Chronic
inflammatory liver diseases and severe decompensatedcirrhosis are often accompanied by behavioral alterations,
including fatigue, mood disorders, cognitive dysfunction,and sleep disturbances. In this section, we review several diseases indicative of the interaction between liver
pathology and neuroimmunity.
Neuroimmune crosstalk in liver pathology
Liver injury

The liver is susceptible to various internal and external
stressors, often resulting in a cascade of events including inflammation, repair, regeneration, and fibrosis.
These processes are typically driven by a chronic inflammatory microenvironment. In studies involving mice,
sympathetic nerve ablation using 6-hydroxydopamine(6-OHDA) prior to carbon tetrachloride ­(CCl4) treatment has been shown to reduce the expression of proinflammatory cytokines, steatosis, and necrosis [122].
Hypertensive rats with increased peripheral sympathetic
activity [123] are more susceptible to C
­ Cl4-induced liver
toxicity, developing cirrhosis after just 4 weeks of ­CCl4
administration, whereas control rats display less severe
bridging fibrosis [124]. When hepatocytes are damaged
by ­CCl4 exposure, they undergo apoptosis, and sympathetic denervation increases hepatocyte apoptosis while
reducing hepatocyte proliferation [125]. Preventing
apoptosis through sympathetic signaling could lead tothe accumulation of damaged cells that produce persistent inflammation and increased fibrosis [125]. Therefore, β-receptor agonists and α1-receptor antagonists
have demonstrated protective effects in models of acetaminophen-induced liver injury [126, 127].
In contrast, parasympathetic neurons exert a protective effect on hepatic inflammation by acting through
α7nACh receptors expressed on macrophages. In studies
involving mice treated with anti-Fas, hepatic vagotomy
significantly increases mortality; however, co-treatment
with an α7nACh receptor agonist attenuates this effect[128]. Vagal signaling also decreases inflammation inPage 11 of 25

LPS-induced hepatitis, likely through macrophageexpressed α7nACh receptors [129]. In murine acetaminophen-induced liver injury, acetylcholinesterase
inhibitors improve survival and reduce hepatocellularinflammation, damage, and apoptosis [130]. Therefore, in
multiple models of chemical liver injury, vagal signaling
plays a protective, anti-inflammatory role, whereas sympathetic neurons promote inflammation and liver damage (Fig. 6A).
Liver fibrosis

Despite advances in research on the pathogenesis andtreatment of liver diseases, effective therapies for liver
fibrosis and cirrhosis remain elusive. Intrinsic parenchymal innervation diminishes in the pre-cirrhotic
liver and is nearly absent in the regenerating nodulesof established cirrhosis [131, 132]. Nevertheless, nerves
persist along fibrous septae and in portal tracts within
pre-cirrhotic and cirrhotic livers [131, 132]. Amongthese, substance P- and neuropeptide Y-positive nerve
fibers tend to predominate over calcitonin gene-related
peptide-containing fibers [133]. An analysis of 178
biopsy specimens from cirrhosis patients revealed concurrent increases in the densities of nerve fibers andmast cells, regardless of the underlying cause. Importantly, these density increases in inflammatory cells andnerve fibers correlated with the degree of liver fibrosisin these patients [134]. Similar findings were observedin a rat model of cirrhosis, where nerve terminals
closely interacted with myofibroblasts in periseptal
sinusoids [135]. In contrast to cirrhosis, which is characterized by widespread hypoinnervation, toxic hepatic
injury specifically induces the proliferation of portal
nerve fibers [136].
The activation of HSCs, also known as transdifferentiation, is the primary source of myofibroblasts that secrete
matrix proteins, thus driving liver fibrogenesis [137].
HSC activation is induced directly or indirectly by paracrine signals from a complex immune and fibrotic microenvironment. Neural signals have long been recognized
as a crucial factor in HSC activation and fibrosis progression. Patients with cirrhosis have elevated blood catecholamine levels and increased sympathetic nerve activity[138]. Studies on toxic injury models suggest that the(See figure on next page.)
Fig. 6 The neuroimmune crosstalk in liver pathology. The sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) playa crucial role in the development and progression of liver diseases, including liver injury (A), liver fibrosis (B), MAFLD (C), and HCC (D). The two 3D
imagines of immunolabeling in the “NAFLD” part are from ref 158. HSCs hepatic stellate cells, HCC hepatocellular carcinoma, IL-6 interleukin 6, MAOA
monoamine oxidase A, MAFLD metabolic dysfunction-associated fatty liver disease, NAFLD non-alcoholic fatty liver disease, PSNS parasympathetic
nervous system, SNS sympathetic nervous system, TNF-α tumor necrosis factor α, 6-OHDA 6-hydroxydopamine, α7nAChR α7 nicotinic acetylcholine
receptor, α/β-R adrenergic cholinergic receptor

Zou et al. Journal of Neuroinflammation

Fig. 6 (See legend on previous page.)(2024) 21:188

Page 12 of 25

Zou et al. Journal of Neuroinflammation(2024) 21:188

SNS acts on nearby HSCs to exert a proinflammatory andprofibrotic effect. Activated HSCs express α-adrenergic,
β-adrenergic, and neuropeptide Y receptors, [139] andcatecholamines induce HSC proliferation and extracellular matrix protein production in vitro [140, 141]. Micelacking dopamine-β-hydroxylase, an enzyme essential for
norepinephrine production, show reduced accumulationof hepatic α-smooth muscle actin when exposed to an
antioxidant-deficient diet that induces fibrosis in control
mice [142].
The role of the PSNS in liver fibrosis has not been fully
investigated. However, the parasympathetic neurotransmitter Ach promotes the proliferation of myofibroblastlike HSCs and induces the expression of collagen genes
in HSCs [143]. These effects are abolished by mecamylamine, an nACh receptor antagonist, suggesting that the
influence of Ach on HSC proliferation is partly mediated through nACh receptors (Fig. 6B) [144]. Advanced
technologies, such as single-cell and spatial multiomics,
multicolor fluorescence, and optogenetics, are needed tobetter understand the role of neuroimmune crosstalk inthe development and progression of liver fibrosis.
Metabolic dysfunction‑associated steatotic liver diseaseNon-alcoholic fatty liver disease (NAFLD) is a hepatic
manifestation of metabolic syndromes and a major risk
factor for liver injury, fibrosis, and even liver cancer [145,146]. NAFLD is currently estimated to affect 38% of the
global population [147] and is expected to become amajor indication for liver transplantation [148] over the
next 20 years. Recently, important conceptual advances
have been made in understanding the complex pathophysiological mechanisms of this highly prevalent livercondition. In 2023, following four rounds of the Delphi
survey, three large multinational liver associations proposed that metabolic dysfunction-associated steatotic
liver disease (MASLD) should replace the term NAFLD[149]; this proposition garnered wide acclaim, albeit
with some dissent [150]. The new nomenclature/criteriaof MASLD is more suited for lean patients with NAFLD
than the previously suggested metabolic dysfunctionassociated fatty liver disease (MAFLD) criteria [151].
This nomenclature change better reflects the pathophysiology and cardiometabolic implications of this common
and burdensome liver disease [152]. Emerging evidence
suggests an excellent concordance rate between NAFLD
and MASLD definitions, with over 99.5% of patients with
NAFLD meeting the MASLD criteria [153]. Younossi
et al. conducted research showing similar clinical profiles and mortality rates for MASLD and NAFLD, which
provided evidence that data generated over the past
three decades for NAFLD can be used interchangeably

Page 13 of 25

for MASLD [154]. Consequently, it is reasonable to consider that the findings and natural history data from older
NAFLD studies remain valid under the new MASLD definition [155].
Increased sympathetic activity is predictive of thedevelopment of metabolic abnormalities, whereas
reduced parasympathetic activity is linked to metabolic
syndrome [156–158]. Autonomic dysfunction is morecommon in patients with NAFLD (MASLD) than those
without [159, 160], suggesting that early autonomic
dysfunction may exacerbate the development and progression of NAFLD (MASLD). Chemical sympathetic
denervation can decrease the expression of gluconeogenic enzymes and peroxisome proliferator activatedreceptor alpha in the liver, reducing high-fat diet (HFD)induced hepatic steatosis [161]. Aging and sympathetic
nerve activity are believed to play significant roles in theaccumulation of liver fat, with the inhibition of sympathetic activity resulting in increased fat accumulation.
The cholinergic anti-inflammatory pathway, regulatedby the vagus nerve, provides protection against inflammation associated with obesity and other metabolic
complications [162]. KCs, which are liver macrophages,
promote liver inflammation through the innate immune
response via toll-like receptor (TLR) signaling. Therefore,
controlling KC activity may inhibit the progression of
NAFLD (MASLD).
Liu et al. used advanced 3D imaging to examine neural
distributions in mice, nonhuman primates, and humanlivers [163]. They observed that neural innervations
within the liver are predominantly sympathetic; moreover, they discovered profound and reversible loss of sympathetic innervations during metabolic challenges. This
hepatic sympathetic neuropathy was induced by TNFα,
produced by ­CD11b+ F4/80+ immune cells in responseto an HFD. The researchers also found that deletingSarm1 alleviated the hepatic sympathetic neuropathy
and improved metabolic parameters in mice challenged
with an HFD. The study revealed that the sympathetic
neurotransmitter norepinephrine suppressed immune
cell inflammation, which otherwise would cause insulin insensitivity in hepatocytes (Fig. 6C). These findings
shed light on a previously unknown neuropathic eventin the liver with metabolic implications [163]. Although
the ANS is intricately connected to and interacts withthe liver, its precise role in the development and progression of NAFLD (MASLD) remains unclear, especiallyin the context of the new MASLD definition. Further
research is strongly encouraged to develop new neuroimmune biomarkers and drugs against MASLD to ensure
patients benefit the most from the changes in disease
nomenclature.

Zou et al. Journal of Neuroinflammation(2024) 21:188

Hepatocellular carcinoma (HCC)

Liver cancer stands as the third leading cause of cancerrelated mortality worldwide, [164] and HCC accounts
for approximately 90% of all liver cancers [165]. The
immune components within the tumor microenvironment of HCC are notably intricate, featuring diverse
populations of myeloid cells and lymphocytes that playroles in inflammation, immune evasion by cancer, andresponses to immunotherapy [166]. HCC is an aggressive
cancer, frequently diagnosed late in the disease course
when effective treatment options are limited. Fortunately,
immunotherapies such as immune-checkpoint inhibitors
are revolutionizing cancer management.
The ANS is being increasingly recognized as a significant contributor to tumor progression and metastasis[167, 168]. High sympathetic fiber density in HCC hepatectomy samples is associated with a poorer prognosis [169]. Monoamine oxidase A (MAOA), an enzyme
involved in catecholamine neurotransmitter breakdown,
is downregulated in HCC, and higher levels of MAOA
are associated with improved and disease-free survival[170]. In a rat model of diethyl nitrosamine-induced
HCC, sympathetic denervation using 6-OHDA reduced
fibrosis and tumor formation [169]. A recent study, combining single-cell RNA sequencing and flow cytometry,
identified ­FOXP3+ ­CXCR3+ mucosal-associated invariant T (MAIT) cells in patients with HCC as regulatory
MAIT cells (MAITregs) with a high immunosuppressive
potential [171]. Additionally, the induction and functionof MAITregs were promoted by β1 adrenergic receptor
signaling in pre-MAITregs and MAITregs, respectively(Fig. 6D). Together, these findings reveal an immunosuppressive subset of MAIT cells that contribute to HCC
progression and suggest a control mechanism throughneuroimmune crosstalk [171].
Liver pathology affecting the CNS
Hepatic encephalopathy

Hepatic encephalopathy (HE), a serious complicationof both chronic liver disease and acute liver failure, isarguably the most clinically relevant entity affecting
the crosstalk between liver immunity and the CNS. HE
manifests in a wide spectrum of neurocognitive abnormalities, ranging from acute severe cases to more chronic
subsyndromal presentations. Patients with fulminant
hepatic failure exhibit rigid extremities (and neck muscles), resistance to passive movements (paratonia), worsening confusion, and agitation. These increased reflexes
can diminish or be lost in patients with progressive deterioration, such as those in a coma [172, 173]. In subacute forms of HE or less severe presentations, patients
may experience frequent falls, fatigue, disinterest, distraction, attention deficits, psychomotor slowing, and,

Page 14 of 25

sometimes, impaired driving abilities. This constellation of less-severe symptoms is termed minimal hepatic
encephalopathy [172, 173]. The metabolic disturbancesand pathogenic mechanisms of HE are multifaceted andcomplex, with key contributing factors believed to be theelevation of blood toxins such as ammonia and the accumulation of inhibitory neurotransmitters due to disturbances in nitrogenous substance metabolism in the gut[174].
Overwhelming evidence demonstrates that the gut
microbiome significantly impacts the crosstalk between
liver immunity and brain function in patients with HE(Fig. 7A) [175–177]. The liver–brain–gut axis represents a complex communication system between the gut
microbiota, the liver, and the CNS. Dysregulation of thisaxis has been implicated in the development of several
metabolic, inflammatory, neurological, and psychiatricdisorders, especially HE [178]. The liver participates inbidirectional communication with the intestine via theportal circulation and bile secretion. Reduced primary
bile acid entering the intestine due to liver disease leads
to alterations in microbiota composition, bacterial overgrowth, and toxic metabolite production, which in turnexacerbate the course of liver disease [179]. Circulating
endotoxins from the gut, together with inflammatory
cytokines produced by the gut microbiome and the liver,aggravate systemic inflammation, modulating the impactof ammonia on the brain [180]. Systemic inflammation
increases the permeability of the BBB and induces neuroinflammation, leading to microglia activation, astrocyte senescence, and neuronal cell death, subsequently
altering neurotransmission and cognitive and motor
function in HE [181–183]. In addition to inflammation,enteric pathogens and their metabolites affect cognitive
behavior through the direct activation of vagal neurons
in the enteric nervous system, altering brain-derived neurotrophic factor, gamma-aminobutyric acid, and oxytocin
signaling in the brain [184].
The importance of gut microbial composition and function in the potential pathogenesis of HE is underscoredby several gut-centric therapies [175]. Fecal microbiotatransplantation, probiotics, prebiotics, and antibiotics
can reduce serum ammonia levels and intestinal-derived
neurotoxic substances by accelerating intestinal transportand changing the metabolism and abundance of intestinal bacteria [176]. A comprehensive understanding of
the mechanisms and importance of the gut–brain–liver
axis is imperative for developing innovative therapeutic
approaches to address HE [185].
Chronic liver disease (CLD)‑associated fatigue

Fatigue is typically the most common complaint and oneof the most distressing symptoms reported by patientsZou et al. Journal of Neuroinflammation(2024) 21:188

Page 15 of 25

Fig. 7 Liver pathology affecting the CNS. The possible mechanisms of how liver pathology affects brain cognitive function in diseases of hepatic
encephalopathy (A), chronic liver disease (CLD)-associated fatigue (B), depression, and anxiety (C). CLD chronic liver disease, CNS central nervous
system, HE hepatic encephalopathy, HCV hepatitis c virus, IFN interferon, NO nitric oxide, PBC primary biliary cirrhosis, TLR2 toll-like receptor 2

with CLD. It is closely associated with alterations inmood, such as anxiety and depression [186]. Fatigue isa multidimensional symptom experienced as tiredness
in the musculoskeletal system, poor recovery from exercise, decreased motivation for usual activities, cognitive

decline, fuzzy thinking, lethargy, and exhaustion [187,188]. CLD-associated fatigue is generally classified into
central (CNS dysfunction, marked by a failure to performvoluntary activities or attentional tasks) and peripheral(neuromuscular failure, characterized by muscle wastingZou et al. Journal of Neuroinflammation(2024) 21:188

and weakness) fatigue. [189]. Although the mechanism
is poorly understood, 55–85% of patients with PBC havebeen reported to present with fatigue, [190, 191] with
20% experiencing significant or life-altering fatigue [192].
Defective release of corticotropin releasing hormone[193, 194] and alteration of serotonergic neurotransmission, mediated by 5-HT receptors [195, 196], have been
implicated in the genesis of central fatigue occurring inan experimental model of cholestatic liver disease [197].
Clinical evidence reveals that fatigued patients with PBC
exhibit stronger resting-state functional neural connectivity between the basal ganglia and motor and premotor cortices, [198] as well as a lower globus pallidus
magnetization transfer ratio, [199] compared to nonfatigued patients with PBC. Communication between
liver pathology and changes in endocrine function andstructure in the CNS is thought to involve two potential pathways: neural and/or humoral. KCs within theliver secrete proinflammatory mediators, subsequently
activating vagal afferent nerves that innervate the liver[186]. Nerve impulses are then carried through the spinal
cord to the brain, thus altering neurotransmission either
directly or indirectly (via microglia activation) [187]. Circulating cytokines from liver inflammation may directlyinteract with cerebral endothelial cells and generate secondary signals (e.g., prostaglandins and nitric oxide),creating a milieu of neuroinflammation, which can activate microglia [200]. Additionally, another immune-toCNS communication pathway was identified, involving
the entrance of immune cells into the brain. Circulating
immune cells were recruited to the brain during liver
inflammation to activate resident immune cells within
the CNS (i.e., microglia) and amplify neuroinflammation [201]. Activation of microglia can reduce synapses
between neurons in the prefrontal cortex of the brain,inhibit neural transduction, and cause behavioral alterations such as anxiety and fatigue [202]. Additionally, theimbalance of manganese homeostasis in the brain as aresult of impaired biliary excretion may be an importantmechanism in the genesis of fatigue in patients with precirrhotic PBC (Fig. 7B) [199].
Fatigue in patients with PBC also has numerous associated peripheral features. Autonomic dysfunction, typically in the form of vasomotor abnormality, is common
at all disease stages of PBC [203]. Autonomic dysfunction
is strongly associated with peripheral fatigue by limiting
the capacity of the muscle to respond through increased
proton/lactate efflux from cells and outflow from tissues [204]. In addition, the anti-mitochondrial antibody
has direct muscle-level metabolic effects, leading toover-utilization of anaerobic metabolism [204]. Other
symptoms of patients with PBC can also indirectly affectthe occurrence of fatigue. Pruritus, another commonly

Page 16 of 25

experienced symptom by patients with PBC, can lead tosleep disorders and worsen the feeling of fatigue [205].
Depression and fatigue are mutually causal and may
share a common pathogenesis [206–208].
Fatigue in PBC has been mostly assessed with subjective and nonspecific versions of numeric ratings or questionnaires, [209, 210], but no consensus on objective or
combined assessments has been reached [188]. Further
work is needed to provide more specific and accurate
methods to quantify the severity of fatigue and distinguish central from peripheral fatigue. Pharmacologicalagents to date have not shown to have a significant, reliable effect in reducing fatigue [211]. Consequently, futurestudies should focus on how the periphery communicates with the brain to mediate changes in central neuralactivity, enabling the identification of novel therapeutictargets to decrease the burden of debilitating fatigue.
CLD‑associated depression and anxiety

Clinical studies have shown that some patients with CLD
also experience mental health issues, such anxiety anddepression, [212] including symptoms such as emotionalsuffering, loss of purpose, and impaired ability to function and complete daily activities. For instance, depression and anxiety have high prevalences in patients with
hepatitis C [213]. Intracerebral neurobiological changes
associated with hepatitis C may potentially explain these
symptoms. These changes may arise from infiltration of
the brain by peripheral cytokines induced by hepatitis C
infection, [214] as well as direct neuropathic effects ofhepatitis C viral particles penetrating the BBB. Peripherally-derived cytokines act on the endothelial cells of
the BBB, stimulating the secretion of secondary messengers such as prostaglandin E2 into the brain [215]. This
stimulates the release of cytokines from activated microglia cells, [216] with subsequent inhibition of neuralconduction in the brain [217]. Human brain endothelial
cells express specific surface functional receptors (claudin-1, tetraspanin CD81, E-2 glycoprotein, and scavenger
receptor-BI) that support hepatitis C viral entry and replication [218]. Viral particles may also be introduced into
the brain via infected mononuclear cells and microglia.
Activated intracerebral microglia harboring hepatitis C
viral infection may have inhibitory or apoptotic effects
on neurons through the release of molecules such as
pregnalone [219]. Furthermore, the hepatitis C virus coreprotein promotes neurotoxicity via the sustained activation of extracellular signal-regulated kinase through tolllike receptor 2 signaling [220]. IL-1β polymorphisms havealso been confirmed to be associated with depressive
symptoms in patients with hepatitis C [221]. Interferons(IFNs), as a highly beneficial therapy in hepatitis C and B,
also bring about many neuropsychological disorders such

Zou et al. Journal of Neuroinflammation(2024) 21:188

as depression, anxiety, and other symptoms that affectthe patient’s quality of life [222]. IFN therapy-related
depression can be explained by several mechanisms,
including its association with inflammation, neurotransmitter imbalance, neurodegeneration and neuroplasticity, and oxidative stress [223, 224]. Future studies should
explore further mechanisms underlying the elevated incidence of depression in patients with hepatitis C, notably
IFN-associated depression (Fig. 7C).
PBC, AIH, and PSC represent the three major autoimmune liver diseases [225]. Depression and anxiety havealso been observed in patients with PBC and AIH [226].
Depression and anxiety in patients with PBC may havea multifactorial basis. Current supported hypotheses
have implicated disrupted neurotransmitter synthesis
and changes in brain structure seen on imaging. Tryptophan, as a precursor for the production of the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]), isoften associated with depressive mood [227–229]. One
study indicated that lower levels of tyrosine and tryptophan were significantly associated with higher levels of
fatigue and unexpected depressive condition [191]. It is
speculated that treatment with steroids could influence
the occurrence of depression and anxiety, since this is awell-known side effect of corticosteroid treatment (Fig. 7)[230, 231].
However, it is still unknown whether depression in turn
alters the structure of liver tissue or even aggravates liverfunction. Further research is needed to identify biomarkers common to both biological processes, to elucidate thepotential biological correlations between depression and
CLD.

Clinical translations
Ongoing research is shedding light on the communication between the nervous and immune systems, with significant implications for clinical applications [91]. Clinicalstudies are exploring novel therapeutic approaches for
inflammatory and autoimmune conditions, including
pharmacological modalities and bioelectronic neuromodulation. Neurotransmitter receptor agonists are a
key pharmacological modality. For instance, the antiinflammatory and disease-ameliorating effects of GTS21, choline, and other α7nACh receptor agonists havebeen demonstrated in murine models of endotoxemia,
sepsis, postoperative brain inflammation, ischemia andreperfusion injury, and various other inflammatory conditions [232–236]. Centrally-acting acetylcholinesterase
inhibitors, such as galantamine, have also been evaluatedas anti-inflammatory agents in endotoxemia, inflammatory bowel disease (IBD), arthritis, and other metabolic
disorders (Fig. 8) [237–239].

Page 17 of 25

Bioelectronic medicine is an emerging area of neuromodulation that aims to identify molecular diseasemechanisms that can be targeted therapeutically usingneural signals and bioelectronic devices. This field isgrounded in the significant role of the vagus nerve in the
inflammatory reflex, which regulates peripheral immune
function and inflammation. The therapeutic potential ofelectrical vagus nerve stimulation (VNS) has been demonstrated in preclinical models of rheumatoid arthritis,[240] IBD, and other inflammatory and autoimmune conditions [238, 241]. Bioelectronic devices, such as VNS,
deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial ultrasound stimulation [242, 243], and splenic nerve
modulation [244], have received clinical approval or are
under investigation for conditions like epilepsy, depression, Alzheimer’s disease, Parkinson’s disease, dystonia,
and other neurodegenerative and neuropsychiatric disorders (Fig. 8). The splenic nerve plays an essential role inmediating the anti-inflammatory effects of VNS in LPSinduced endotoxemia [245, 246]. It has been reported
that the anti-inflammatory efficacy of nerve stimulation might be improved by directly targeting the splenic
nerve instead of the vagus nerve [247, 248]. An interesting animal study verified that splenic nerve denervation could inhibit LPS-induced depression-like behavior[244]. Collectively, research suggests a role for splenic
nerve modulation in inflammation-induced abnormalities. Afferent and efferent vagus nerve signaling may contribute to communication between the brain and spleen(the brain–spleen axis), which may also indirectly participate in regulating liver functions that affect health [249].
Therefore, splenic nerve modulation as a potential therapeutic approach provides new insights into the treatmentof liver diseases.
Recent progress in understanding the role of neuralpathways in controlling inflammation and other physiological functions, along with advances in neuromodulatory technologies, including electrodes, physiologicalinterfaces, and devices, have paved the way for clinicaltranslation of this knowledge. However, several criticalconsiderations must be addressed for clinical translation.
First, evaluating intersubject variability in innervationand neuron origins across different species is essential
for designing effective therapies that target specific cell
populations. Additionally, understanding the influence ofchronic inflammation on organ innervation is crucial, as
it can lead to neural changes like sprouting, hypertrophy,
and altered neurotransmitter release, affecting neuraldensity and function. These gaps highlight the need forongoing preclinical and clinical studies to assess inflammation’s effects on organ innervation. Lastly, a deeper

Zou et al. Journal of Neuroinflammation(2024) 21:188

Page 18 of 25

Fig. 8 The Clinical translations and future directions of the neuroimmune crosstalk in the liver. DBS deep brain stimulation, IBD inflammatory bowel
disease, TMS transcranial magnetic stimulation, tDCS transcranial direct current stimulation, TUS transcranial ultrasound stimulation, VNS vagus
nerve stimulation, α7nAChR α7 nicotinic acetylcholine receptor

understanding of the neural circuitry components that
regulate specific biological processes is vital for the fieldof neuroimmune medicine, enabling the simultaneoustargeting of multiple sites. Achieving this will require
collaborative efforts across various disciplines, including molecular medicine, immunology, biophysics, bioengineering, biochemistry, materials science, mechanicalengineering, electrical engineering, computer science,
mathematics, and artificial intelligence (Fig. 8).

Conclusions and perspectives
The nervous and immune systems hold pivotal roles inmaintaining bodily regulation and defense. In this review,
we have explored the experimental evidence showcasing

Zou et al. Journal of Neuroinflammation(2024) 21:188

the intricate interplay between these two systems in thecontext of liver diseases. As neuroscience and immunology progress, our understanding of the molecularmechanisms governing immune regulation undergoes a
profound transformation. Delving into the mechanismsof neuroimmune communication has not only expanded
our knowledge but has also paved the way for the evaluation of innovative therapeutic approaches. These
approaches, including pharmacological modalities andbioelectronic medicine, have shown promise in preclinical and clinical settings for conditions like sepsis, IBD,
and arthritis.
However, it is worth noting that neuroimmune-mediated therapies for liver diseases are still in their infancy.
While local neuroimmune interactions have been extensively studied, comprehensive techniques that provide aholistic view of neuroimmune interactions between distant organs and the nervous system in vivo are currently
limited. Additionally, the molecular mechanisms governing local immune regulation within the nervous systemremain elusive.
The future of this field holds immense promise as
cutting-edge technologies, such as multiomics, “multitissue” organoids, optogenetics, and single-cell and spatial transcriptomics, are shedding light on more precise
anatomical connections and functional interactions
within the neuroimmune network. These advancements
will continue to unveil new insights into the anatomicaland functional foundations of neuroimmune units at anorganismal level.
In conclusion, ongoing research in the field of neuroimmune interactions promises to unravel the mysteries of
how these systems collaborate and will likely yield effective therapeutic strategies for liver diseases and beyond.
This interdisciplinary journey, bridging neuroscience,
immunology, and advanced technologies, heralds a hopeful future where our understanding of neuroimmune
communication transforms into tangible clinical benefits.
Abbreviations
ACh	Acetylcholine
AIH	Autoimmune hepatitis
ANS	Autonomic nervous system
AVP	Arginine-vasopressin
CCl4	Carbon tetrachloride
CLD	Chronic liver disease
CNS	Central nervous systemDCs	Dendritic cells
GI	Gastrointestinal
GLP-1	Glucagon-like peptide 1
HCC	Hepatocellular carcinoma
HE	Hepatic encephalopathy
HFD	High-fat diet
HSCs	Hepatic stellate cells
IBD	Inflammatory bowel disease
IFN	Interferon
KCs	Kupffer cells
ILC3s	Group 3 innate lymphoid cell

Page 19 of 25

LPS	Lipopolysaccharide
MAFLD	Metabolic dysfunction-associated fatty liver disease
MAIT	Mucosal-associated invariant T
MAITregs	Regulatory MAIT cells
MAOA	Monoamine oxidase A
MASLD	Metabolic dysfunction-associated steatotic liver disease
NAFLD	Non-alcoholic fatty liver diseaseNK	Natural killer
P2Y6	UDP-specific type 6 purinergic
PBC	Primary biliary cholangitis
PKC	Protein kinase C
PNS	Peripheral nervous system
PSC	Primary sclerosing cholangitis
PSNS	Parasympathetic nervous systemSNS	Sympathetic nervous system
TRPV4	Transient receptor channel protein vanilloid 4
TNF	Tumor necrosis factor
VIP	Vasoactive intestinal peptide
VIPR2	Vasoactive intestinal peptide receptor 2
5-HT	5-Hydroxytryptamine
6-OHDA	6-Hydroxydopamine
Acknowledgements
We would like to thank Editage for English language editing.
Author contributions
Ruochan Chen: conceptualization, investigation, and writing (original draft,
review & editing). Ju Zou: writing and graphics (original draft, review andediting). Jie Li, Xiaoxu Wang, and Daoling Tang: writing (original draft, review
and editing).
Funding
This manuscript was supported by grants from the National Natural Sciences
Foundation of China (82070613 and 82370638 to R.C.), the Science and Technology Innovation Program of Hunan Province (2022RC1212 to R.C.), and the
Natural Science Foundation of Hunan Province China (2023JJ10095 to R.C.).
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 11 December 2023 Accepted: 19 July 2024

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