(2023) 9:24
Tanaka et al. Bioelectronic Medicine
https://doi.org/10.1186/s42234-023-00126-1

Bioelectronic Medicine

Open Access

REVIEW

Gateway reflexes describe novel
neuro‑immune communications that establish
immune cell gateways at specific vessels
Hiroki Tanaka1*, Rie Hasebe1,2, Kaoru Murakami1, Toshiki Sugawara1, Takeshi Yamasaki1,2 andMasaaki Murakami1,2,3,4*   

Abstract
Neuroinflammation is an important biological process induced by complex interactions between immune cells
and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication
between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood
brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex
in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords
and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal bloodvessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several
environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter
immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune
diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases.
Keywords Neuro-immune communication, Immune regulation, Inflammation, Blood-brain barrier, IL-6 amplifier*Correspondence:
Hiroki Tanaka
htanaka@igm.hokudai.ac.jp
Masaaki Murakami
murakami@igm.hokudai.ac.jp
1
Division of Molecular Psychoimmunology, Institute for Genetic Medicine
and Graduate School of Medicine, Hokkaido University, Kita‑15, Nishi‑7,
Kita‑Ku, Sapporo 060‑0815, Japan
2
Division of Molecular Neuroimmunology, National Institutefor Physiological Sciences, national Institute for Natural Sciences, Nishi‑38,
Myodaiji‑cho, Okazaki, 444‑8585, Japan
3
Group of Quantum Immunology, Institute for Quantum Life Science,
National Institute for Quantum and Radiological Science and Technology(QST), Anagawa 4‑9‑1, Inage‑Ku, Chiba, 263‑8555, Japan
4
Institute for Vaccine Research and Development (HU‑IVReD), Hokkaido
University, Nishi‑11, Kita‑21, Kuta‑Ku, Sapporo 001‑0020, Japan

Introduction
The central nervous system (CNS), which includes thebrain and spinal cord, is a unique system with neural connections across several organs and physiological systems(Mai and Paxinos 2011). Bidirectional communication of
the CNS with the periphery, such as endocrine systems,
digestive organs, gut microbiota, and immune systems,
transduce sensory stimuli under psychological disorders
into physiological outputs via neural signaling and hormones. In the case of the immune system, chronic psychological stress induces the release of neurotransmittersfrom axon terminals that can act as paracrine regulatorsof immune responses including the CNS (Morey et al.
2015).

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Tanaka et al. Bioelectronic Medicine(2023) 9:24

The CNS is anatomically segregated from other systems
and organs by two types of tight barriers: the blood-cerebrospinal fluid (CSF) barrier and the blood-brain barrier(BBB) (Ransohoff and Engelhardt 2012). The blood-CSF
barrier forms an apical tight junction between choroid
plexus epithelial cells, while the BBB forms a more complicated network of multiple tight junctions between thebasal membranes of epithelial cells on brain microvessels(Engelhardt and Sorokin 2009). Immune cells circulate inlymph and blood vessels to perform immunosurveillanceagainst tumor development, bacterial, and viral infection
even in the CNS, although their access to the CNS is significantly limited by the BBB. Cells including microglia
within the CNS parenchyma exhibit low MHC class II
expression, indicating that the CNS establishes a specialized environment in which T cells are difficult to activate(Bö et al. 1994). T cells are one of the main causes of tissue inflammation and autoimmunity and exist in the CSF(Kivisakk et al. 2003). The presence of the BBB suggeststhat the CNS is an immune-privileged site and that theadaptive immune system is severely restricted there.
However, recent studies have challenged this idea about
the immune privilege of the CNS. The CNS is a common
target of viral infections and autoimmune neuroinflammatory diseases (Korn and Kallies 2017). The self-antigens released from damaged parenchymal CNS tissues
are drained into lymphoid organs through the CSF, leading to neurodegeneration and neuroinflammation (Locatelli et al. 2012). Furthermore, immune cells encountermany blood vessels in the CNS after they recognize
parenchyma-derived antigens drained from the CNS(Louveau et al. 2015). These findings highlight the importance of immune cells in the CNS during immunosurveillance as well as the development of neuroinflammation.
The gateway reflex is a new concept of neuro-immune
interactions, in which immune cells, including autoreactive CD4+ T cells, respond to CNS antigens in the blood
via formation of ‘the gateway’ for immune cell in bloodvessels (Kamimura et al. 2020; Uchida et al. 2022). Additionally, recent studies have revealed that the gateway
formation leads to different types of biological response
from autoimmunity. In this review, we describe the structural and functional feature of the gateway reflex andhow it connects specific neural activation depending
on external or internal stimuli to modulate the immune
responses.

T cells and neural circuits in the CNS
Experimental autoimmune encephalomyelitis (EAE) is a
widely used model for multiple sclerosis (MS), which isa neuroinflammatory disease characterized by focal lymphatic infiltration and demyelination in the CNS followedby the development of neurological and psychiatricPage 2 of 11

disorders (Constantinescu et al. 2011). In EAE, the immunization of CNS antigens with their peptide fragments orwhole proteins, such as myelin-derived proteins, induces
the expansion of autoimmune myelin-specific CD4+ T
cells followed by neuroinflammation development. The
autoreactive CD4+ T cells highly express chemokine
receptors and cell adhesion molecules to interact withchemokines and ICAM1 on the endothelial cells of thegateway of immune cells and to infiltrate infiltrate fromblood vessels into the CNS (Yednock et al. 1992). T cell
migration across the BBB is followed by infiltration in
the CNS and the development of neuroinflammation.
Neuroinflammation in the CNS leads to the dysregulation of neuronal circuits around myelinated spinal axonsand progressive clinical signs such as tail and hindlimb
paralysis (Constantinescu et al. 2011). EAE pathology
appears not only by the immunization of myelin-derived
peptides (active EAE model), but also by the intravenoustransfer of activated myelin-specific CD4+ T cells, which
are re-stimulated in vitro with myelin oligodendrocyte
glycoprotein (MOG) peptide, into wild-type C57BL/6
mice (adoptive transfer EAE (tEAE) model) (Stromnes
and Goverman 2006). In tEAE, ­TH17 cells, a subset of
activated CD4+ T cells, are required for EAE progression(Langrish et al. 2005). Myelin-specific T­ H17 cells from
immunized mice or transgenic mice with MOG peptidespecific TCR can be maintained and expanded in vitro by
TCR signaling via antigen presentation in the presenceof interleukin (IL)-23, which is required for the survivalof ­TH17 cells (Stromnes and Goverman 2006; Jager et al.
2009). Activated T­ H17 cells highly secrete proinflammatory cytokines, including IL-17, TNF-α and IL-6, which
contribute to the inflammatory response of nonhematopoietic cells by synergistically amplifying inflammation in combination with the simultaneous activation of
STAT3 and NFkB (Ogura et al. 2008; Shen et al. 2006).
A mechanistic scheme involving T­ H17 cell-associatedinflammation around the BBB is a widely acceptedhypothesis for how autoreactive T cells by this boundary cause autoimmune diseases (Hirota et al. 2007; Liston
et al. 2009).
Numerous studies have demonstrated the pivotal roleof ­TH17 cells and IL-17 in the pathogenesis and development of chronic autoimmune diseases, and clinical strategies have accordingly been adopted to target T­ H17 cells
and IL-17 (Miossec and Kolls 2012; Gaffen et al. 2014).
In chronic inflammation, IL-17 enhances the innate
immunity of nonhematopoietic cells, such as synovial
fibroblasts for rheumatoid arthritis, keratinocytes forpsoriasis, and vascular endothelial cells in EAE (Kimet al. 2007; Arima et al. 2012; Furue et al. 2020). Although
IL-17 is a relatively weak activator of the NK-κB pathway, its cooperative stimulation with IL-6 leads to theTanaka et al. Bioelectronic Medicine(2023) 9:24

overproduction of cytokines and chemokines in a feedback loop of NK-κB and STAT3, a phenomenon termed
the IL-6 amplifier (Ogura et al. 2008; Lee et al. 2012).
Cytokines, chemokines, and growth factors in this inflammatory cycle promote the accumulation of immune cells,
including pathogenic ­TH17 cells, into local inflammatory
lesions, accelerating local damage to peripheral organs.
Thus, the IL-17-mediated positive feedback of inflammation provides insights into the mechanism underlying theexacerbation of chronic diseases associated with ­TH17
cells. Along with IL-17, activated CD4+ T cells express
IL-6 and TNFa, two NF-kB activators that enhance theIL-6 amplifier (Ogura et al. 2008; Lee et al. 2012). The
IL-6 amplifier induces a massive release of several typesof chemokines and growth factors from nonhematopoietic cells in Rheumatoid arthritis and EAE model(Harada et al. 2015), able to attract inflammation-associated immune cells such as T cells, neutrophils, inflammatory monocytes, and macrophages and to promote
overgrowth of fibroblasts in affected tissues. These severe
inflammation causes ankylosis in the large joints (Atsumi
et al. 2002). So the prolonged and amplified inflammation of nonhematopoietic cells by the IL-6 amplifier will
become fundamental concept to understand the complex
mechanism of tissue destruction during disease onset
and development of autoinflammatory diseases.
Nervous systems orchestrate most physiological processes to maintain cell and tissue homeostasis. The disturbance of neural circuits can cause the dysfunctionof multiple systems including the immune system. For
example, the hypothalamic-pituitary-adrenal (HPA) axis
releases glucocorticoids systemically upon psychological stresses; these hormones suppress immune cell functions (Bellavance and Rivest 2014). Another example is
how the stress mediator corticotropin-releasing hormone(CRH) induces mast cell degranulation and enhances
vascular permeability in skin tissue (Theoharides et al.
1998). CRH also activates skin fibroblasts and keratinocytes to release several inflammatory mediators that
selectively suppress ­TH1 responses and promote a skewing toward allergic ­TH2 responses (Arck et al. 2006).
The vagus nerve pathway mainly provides parasympathetic innervation to digestive and endocrine organs.
Notably, this pathway induces the anti-inflammatory
vagal reflex by releasing neurotransmitters from thevagus nerve to immune cells (Breit et al. 2018; Bonaz et al.
2016). Additionally, neural activation under physiologicalstress indirectly affects vascular inflammation through T
cell activation. Finally, psychological stresses activate therenin-angiotensin-aldosterone cascade to release angiotensin II, a strong activator for T cells, which produce theseveral cytokines required for vascular inflammation andimmune cell recruitment (Dinh et al. 2014; Guzik et al.

Page 3 of 112007). Previous studies demonstrated an association of
the sensory nerve pathway with regulation of inflammatory processes via an antidromic way. Indeed, antidromic
stimulation of capsaicin-sensitive vagal and splanchnic
afferent (C- and Aδ-fibers) pathways results in the releaseof neuropeptides such as calcitonin gene-related peptide(CGRP) from sensory nerve axon terminal (Holzer 1988).
These substances have a dual role in inflammation, they
contribute to protective reflexes in the gastrointestinal
and nasal mucosa (Holzer 1991), while the innervation
via efferent and afferent/sensory fibers rather than vagus
nerves is important for protection of gut in DSS-induced
mouse colitis model (Willemze et al. 2018).

Gateway reflex
The gateway reflex is a group of neural and immune
responses that create gateways at specific blood vessels
for immune cells to infiltrate nervous systems. They regulate local neuroinflammation and affect neuro-immune
functions as well as some clinical aspects of neuroimmune diseases.
Gravity gateway reflex

Weight-bearing muscles, joints, and bones are affectedby gravity. Soleus muscles, which are anti-gravity muscles
and necessary to maintain posture for weight-bearing,
continuously stimulate neural circuits in both humans
and mice. Dorsal root ganglia (DRG) at the fifth lumbar
spinal cord (L5) spinal cord are innervated by sensory
neurons of the soleus muscles. Gravity stimulation canconstantly activate the neighboring spinal cords of dorsal
vessels through the innervation of sensory neurons fromthe L5 DRG to create the gravity gateway reflex via thesympathetic pathway from L5 sympathetic ganglions.
To explore how autoreactive CD4+ T cells against
myelin-peptides accumulate in the CNS, we employed
the tEAE model, a mouse model for MS induced by the
intravenous injection of MOG-primed CD4+ T cells(Langrish et al. 2005; Ogura et al. 2008). The disease intEAE develops in a similar fashion as that in the active
EAE model, including the loss of tail tonicity and development of hindlimb paralysis, despite tEAE being free ofcomplete Freund’s adjuvant and pertussis toxin. Given
the widespread distribution of myelin in the CNS andperivascular circulation of myelin-specific autoreactive
CD4+ T cells, there exists a unique entrance site to the
CNS for these T cells. We found that myelin-specificCD4+ T cells preferably accumulate in the dorsal vesselsof the L5 cord at the onset of EAE symptoms (Arima et al.
2012) (Fig. 1). The accumulation of these CD4+ T cells
induces strong inflammation around the L5 dorsal vessels to drive the IL-6 amplifier. CCL20, a chemokine that
attracts CCR6-expressing immune cells, such as ­TH17

Tanaka et al. Bioelectronic Medicine(2023) 9:24

Page 4 of 11

controls regional blood vessels to produce cytokinesand chemokines, leading to the accumulation of autoreactive T cells in the blood, their entry into the CNS,
and the development of an MS-like pathogenesis. As
well as myelin-specific CD4+ T cells, myelin-specificCD8+ cytotoxic T cells can infiltrate into the CNS andinduce brain neuroinflammation, although the major
sites for their entry are located at brain but not at the
spinal cord (Huseby et al. 2001). This indicates the different mechanism of CD8+ T cell entry into the CNS.
Pain‑induced gateway reflex

Fig. 1 Gravity gateway reflex. Gravity activates sensory nervesin the soleus muscle, whose cell bodies are located at the dorsal
root ganglion of the fifth lumbar (L5) spinal cord (upper). The
retrograde activation of sensory nerves propagates into sympathetic
ganglions via an unknown pathway to release norepinephrine(NE) from the peripheral axons of sympathetic nerves to L5 dorsal
blood vessels. NE amplifies inflammation initiated by autoreactive(MOG-specific) T cells at the L5 blood vessels in an IL-6
amplifier-dependent manner. It also enhances the release of CCL-20
and infiltration of autoreactive T cells inside the CNS (bottom)

cells (Hirota et al. 2007; Borgne et al. 2006), is released
from the inflamed dorsal vascular endothelial cells, promoting the assembly of myelin-specific CD4+ T cells at
L5 dorsal vessels.
Suspending mice by their tails unloads the hindlimbs
to reduce gravity stimulation to the soleus muscles.
Tail suspension significantly reduced T cell numbers
and CCL20 production in L5 dorsal endothelial cells
during tEAE onset (Arima et al. 2012). Tail suspension also inhibited the expression of c-fos, an indicator of neural activation, in L5 DRG (Arima et al. 2012).
This immunosuppressive effect is canceled by the electrical stimulation of the soleus muscles, resulting in
CCL20 expression from the L5 dorsal vessels of tEAE
mice even with tail suspension (Arima et al. 2012).
Gravity stimulation released norepinephrine (NE), a
neurotransmitter and NFkB stimulator, from sympathetic neurons around the L5 dorsal vessels to induce
inflammatory cytokines via the IL-6 amplifier (Arimaet al. 2012) and enhance inflammation by increasing
the release of CCL20 in endothelial cells of the L5 dorsal vessels (Fig. 1). Thus, the gravity gateway reflex isa mechanism by which sensory-sympathetic crosstalk

Pain is an unpleasant sensory and emotional experience associated with actual and potential tissue damage (Raja et al. 2020). Upon a peripheral injury, immune
cells can activate nociceptors on neuronal axons to
express inflammatory mediators that trigger pain signals and tissue inflammation (Ren and Dubner 2010).
We found that pain induction by the partial ligationof the middle part of the trigeminal nerve induces therecurrence of EAE during the remission phase in tEAE
(Arima et al. 2015) (Fig. 2). Pain stimuli are delivered
to the anterior cingulate cortex (ACC), which has neurons related to pain sensation, and subsequently activate sympathetic circuits distributed to ventral vesselsof the spinal cord, creating the pain-induced gateway at specific sites around the L5 spinal cord during
the remission phase of EAE (Arima et al. 2015). Afterthe pain sensation, NE is released from sympathetic
axons around whole ventral vessels of the spinal cordto activate the IL-6 amplifier. Because there are MHC
class II+ monocytes at the L5 sites that accumulated
from the blood during the initial disease development,
CX3CL1 secretion from the vessels and MHC class
II+ monocytes themselves accumulate MHC class II+
monocytes around the L5 ventral vessels to increase
vessel permeability. Circulating MOG-specific autoreactive CD4+ T cells in the blood also accumulate at theL5 ventral vessels to develop EAE relapse (Arima et al.
2015) (Fig. 2). The numbers of inflammatory monocytes
accumulated to peripheral of the meninges of the spinal cords have a correlation of the disease severity of
EAE (Ajami et al. 2011), supporting our findings with
MHC class II+ monocytes accumulation required for
EAE relapse. Thus, pain stimuli during the remission
phase of tEAE established immune cell-gateways in thepresence of MHC class II+ monocytes in the L5 cord.
Notably, MS patients show a very characteristic pattern of periodic relapse followed by remission (Steinman 2014). Therefore, the proposed mechanism of thepain-gateway reflex may explain the clinical pattern of
relapse and remission in MS patients.

Tanaka et al. Bioelectronic Medicine(2023) 9:24

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Fig. 2 Pain-induced gateway reflex. Upon sensing pain, sensory nerves propagate activation signals to the anterior cingulate cortex (ACC),
a key region for pain processing in the brain. This activation finally reaches the L5 vertebrate via sympathetic nerves to induce CX3CL1 releasefrom ventral blood vessels in a norepinephrine-dependent manner. CX3CL1 recruits MHC class I­Ihi monocytes around the ventral vessels. In EAE
mice experiencing remission 20 days after the intravenous injection of MOG specific CD4+ T cells, pain stimulation induces the re-activationof MOG-specific CD4+ T cells at the ventral vessels and their infiltration into the CNS followed by the relapse of EAE disease symptoms with CNS
neuroinflammation

Stress gateway reflex

Chronic stresses are known to be a significant risk factor
for gastrointestinal, cardiovascular, and autoimmune diseases. Anxiety, depression, and posttraumatic stress disorder progressively increase a risk of inflammatory bowel
diseases in a national cohort of US veterans (Thakur et al.
2020). Chronic stresses include those that activate neuralpathways toward the paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), dorsal motor nucleus of
the vagus verve (DMX), and vagus nerves (Ulrich-Lai andHerman 2009). Efferent activation of the parasympathetic
and vagal nerves under psychological stresses develops
the gut-associated inflammation in acute and chronic
gastroenteritis (Browning and Travagli 2014; Kenney andGanta 2014). Accordingly, we investigated the chronic
stress-mediated gateway reflex in the tEAE model. For
this experiment, we employed sleep disturbance stress(SDS) and stress induced by an unfavorable circumstance, where an individual mouse was housed in thespecial cage for providing perpetual avoidance of water
on a wheel (PAWW) stress (Miyazaki et al. 2013). tEAE

mice under these chronic stresses did not exhibit any
typical symptoms of the EAE pathology, such as hindlimb
paralysis, but they did show acute upper gastrointestinal
failure with the removal of epidermal and mucus layers
and bloody stool. Additionally, they exhibited an increasein blood potassium ion concentration, leading to fatal
cardiovascular damage with sudden death (Arima et al.
2017) (Fig. 3). Because there was almost no autoreactive
CD4+ T cells in the L5 cord, we concluded that chronic
stress opened a different immune cell gateway from theone caused by gravity. In the stressed tEAE model, autoreactive CD4+ T cells had accumulated at blood vessels
adjacent to the dentate gyrus, thalamus, and third ventricle. Additionally, dopaminergic (tyrosine hydroxylase
positive; TH+) neurons distributed around specific bloodvessels were activated in the PVN, a direct stress responsesite (Arima et al. 2017). The activated neurons secreted
NE to stimulate the IL-6 amplifier at the specific vessels
to recruit autoreactive CD4+ T cells from blood together
with MHC class IIhi monocytes followed by the amplification of local inflammation. Microinflammation aroundTanaka et al. Bioelectronic Medicine(2023) 9:24

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Fig. 3 Stress-induced gateway reflex. Chronic mental stresses sequentially activate neurons in the paraventricular nucleus of the hypothalamus(PVN) and tyrosine hydroxylase neurons connecting specific vessels adjacent to the third ventricle, dentate gyrus, and thalamus. This neuralactivation induces the CCL5-expression-dependent accumulation of CD4+ T cells and MHC class I­Ihi monocytes followed by microinflammationin specific brain vessels. The microinflammation activates the dorsomedial nucleus of hypothalamus (DMH) via neural connections, propagates
activation signals to dorsal motor nucleus of the vagus nerve (DMX), and finally causes upper severe gastrointestinal (GI) tract failure. Bleedingfrom the upper GI tract elevates blood potassium ion levels, which are associated with myocyte apoptosis and an increased mortality in acute heart
failurethe blood vessels released extracellular ATP, which acts
as a neurotransmitter for DMX neurons around specificvessels through ATP receptors (Fig. 3). In the stress gateway reflex, microinflammation at specific vessels in thebrain and the ATP-induced neural activation stimulated
the vagus nerve pathway, which caused epithelial damage in the stomach through the acetylcholine-dependent
overproduction of gastric acid. The epithelial cell damage induced bleeding at the upper gastrointestinal tract
and the acute elevation of cytosolic potassium ions, followed by sudden cardiac dysfunction and death. PVN
and DMH are also key regulators of circulatory control
by regulating blood pressure (Guyenet 2006). Activationof sympathetic nervous system under chronic stresses
will assist elevated blood pressure and contribute to thestress-induced mortality by promoting the bleeding at GI
tract. Thus, chronic stress is a key factor in the bidirectional communication between the nervous and immune
systems. Brain neuroinflammation is a strong risk factor
for the development of neurodegenerative disease including Alzheimer’s disease, non-Alzheimer’s dementia, Parkinson’s diseases, and epilepsy (Chen et al. 2016; Lull andBlock 2010). We have also demonstrated that inflammation at specific blood vessels of the brain during thestress gateway reflex is an important prognostic factor for
acute gastrointestinal diseases and cardiovascular death(Arima et al. 2017).
Light gateway reflex

Uveitis is an autoimmune disease with inflammationand tissue damage mediated by autoreactive CD4+ T
cells in the retina and choroid and can lead to significant
visual deficiency and blindness if untreated (Caspi 2010).
Experimental autoimmune uveitis (EAU) is a mousemodel for human uveitis (Caspi 2010; Caspi 2003). EAU
is induced by immunization with a peptide antigen
derived from human photoreceptor retinoid binding protein (hIRBP) with complete Freund’s adjuvant and pertussis toxin. hIRBP-specific (uveitogenic) CD4+ T cells
infiltrate the retinal tissue across the blood-retina barrier,which is the retina’s blood barrier, to cause progressive
inflammation in the retina (Stofkova et al. 2019). In EAU,
activated uveitogenic T cells accumulate in retinal bloodvessels 10 days after immunization, where immune cells

Tanaka et al. Bioelectronic Medicine(2023) 9:24

form gateways in the retina (Stofkova et al. 2019). However, mice with EAU pathology showed fewer T cells in
the retina after exposure to photopic light, which stimulates strongly neurons in retina tissues (Stofkova et al.
2019). Photopic light during EAU inhibits adrenergic
receptor expression on endothelial cells of retinal bloodvessels, making these cells less sensitive to NE, thus
reducing inflammation and cytokine production and failing to activate the IL-6 amplifier. It is known that bright
light has protective effects on retinal nerves and photoreceptors by producing neuroprotective cytokines andantioxidants from damaged cells (Fig. 4) (Organisciak
and Vaughan 2010). Thus, our model revealed the role ofphotopic illumination in protecting retinal organs fromautoreactive T cell infiltration to prevent neuroinflammation and tissue damage. The light gateway reflex is a novel
gateway reflex, because it negatively regulates injured
vascular endothelial cells to provide a protective role.
Remote inflammation gateway reflex

Inflammatory arthritis, including rheumatoid arthritis and psoriatic arthritis, are characterized by joint
inflammation, joint swelling, pain at the joints, anddestruction of synovial joints (Aletaha et al. 2010). Ina certain group of inflammatory arthritis patients, joint
inflammation occurs bilaterally along the affected joints(Aletaha et al. 2010; Guo et al. 2018). Consistently, several animal models of rheumatoid arthritis often show
bilateral spreading inflammation within joints (Atsumi
et al. 2002; Sakaguchi et al. 2003; Tuncel et al. 2016).
Some studies have suggested the important role ofneural pathways in the bilateral spread of inflammation during arthritis development (Donaldson et al.
1995; Kidd et al. 1989). We revealed that neural pathways connecting both ankle joints are critical for the

Page 7 of 11

inflammation spreading in a symmetrical manner. We
defined these neural pathways as the remote inflammation gateway reflex (Hasebe et al. 2022). ­gp130F759/
F759(F759) mice are a mouse model that spontaneously
develops rheumatoid arthritis in which joint inflammation is amplified by the IL-6 amplifier (Ogura et al.
2008; Atsumi et al. 2002). In F759 mice, arthritis can be
rapidly induced by administering IL-6 and IL-17A to
the joints (Harada et al. 2015; Murakami et al. 2011).
In the remote inflammation gateway reflex, the bilateral spread of inflammation is accomplished by neuralcrosstalk between sensory and interneurons that utilize ATP both as a neurotransmitter and as an inflammation enhancer. To test how inflammation-induced
neural activation is transmitted through neural circuits
and expanded to the peripheral sites, we employed
two arthritis models, F759 mice and type II collagenimmunized mice, with priming arthritic inflammation and neural activation between both ankle joints(Hasebe et al. 2022). ATP released from non-immune
cells during inflammation stimulated sensory pathways.
The activation signal in neurons propagated primarily
through neural circuits composed of Nav1.8+ sensory
neurons and proenkephalin+ interneurons to reach thecontralateral ankle joints, in which ATP was released
from the sensory axon and promoted inflammation via
the IL-6 amplifier (Fig. 5). An ATP receptor antagonist(A438079) or surgical dissection of Nav1.8+ sensory
and proenkephalin+ interneuron networks successively
inhibited the symmetrical spread of inflammation inthese models (Hasebe et al. 2022). These results have
only been demonstrated in mice but encourage further studies to explore therapeutic targets to treat diseases with symmetrical inflammation spreading such as
rheumatoid arthritis.

Fig. 4 Light gateway reflex. The retinal inflammation found in experimental autoimmune uveitis (EAU) model mice is strongly attenuatedby photopic light illumination. Photopic light stimulation induces the excessive release of norepinephrine (NE) and epinephrine (Epi) from retinal
neurons to retinal blood vessels, resulting in the downregulation of α1A adrenergic receptors. In retinal blood vessels, NF-κB and STAT-3 activation
is inhibited, and IL-6 production is reduced. This suppressive response contributes to a reduced number of immune cells infiltrating the retina, thus
attenuating EAUTanaka et al. Bioelectronic Medicine(2023) 9:24

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Fig. 5 Remote inflammation gateway reflex. A schematic model of the remote gateway reflex in the symmetrical spread of inflammatory lesions.
The stimulation of collagen type I+ ankle nonhematopoietic cells from gp130 Y759F mutant (F759) mice with proinflammatory cytokines IL-6
and IL-17 strongly activates NF-κB and STAT-3 in an IL-6 amplifier-dependent manner, releasing extracellular ATP as a neurotransmitter. Sensory
activation primed by sensitization to the ATP receptor P2X7 propagates from one side of the DMX to the other side through nerve networks
comprised of sensory neurons and proenkephalin+ interneurons. Sensory stimulations arriving at the contralateral terminal promote ATP releasefrom the sensory nerves to drive NF-κB and STAT-3 activation-mediated inflammation in collagen type I+ nonhematopoietic cells locatedat the contralateral side of the original inflammatory lesions

Immunological and behavioral modification of SLE model
mice under stress

Systemic lupus erythematosus (SLE) is an autoimmune
disease attributed to the loss of immunological tolerance with many symptoms including skin rash, arthritis,
nephritis, hematologic abnormalities, and inflammationin the CNS (Tsokos 2011). About half of SLE patientsshow some kind of neurological and psychiatric symptoms, including headaches, mood disorder, anxiety,and mild cognitive disfunctions, which are diagnosed
as neuropsychological SLE (NPSLE) (Schwartz et al.
2019). NPSLE is further classified into focal neurological syndrome-type NPSLE (fNPSLE) and diffuse neurological-psychiatric-cognitive syndrome-type NPSLE(dNPSLE) (Ellis and Verity 1979). dNPSLE is diagnosedin 80% of NSLE patients and is characterized by diverse
clinical manifestations including cerebrovascular disease, seizure disorder, acute confusional state (ACS), andneuropathies. It is hypothesized that most cases havedysregulated neural circuits caused by autoimmunity andautoinflammatory conditions in the CNS, but there is
still no NPSLE mouse model to study the disease. On theother hand, several mouse models exist for the disease
manifestation and pathogenesis of human SLE. MRL/
MpJlpr/lpr (MRL-lpr) mice spontaneously develop autoimmune cell infiltration and systemic inflammation in multiple organs (Theofilopoulos and Dixon 1985; Vogelweid
et al. 1991). We hypothesized that chronic stress, suchas SDS, in this SLE model causes NPSLE-like behaviors.

Notably, MRL-lpr mice under SDS display risk-taking
agitation-like behavior, less anxiety-like behavior, hyperactivity, and psychomotor agitation compared with mice
without stress (Abe et al. 2022). Further, SDS activates
microglia in the medial prefrontal cortex (mPFC), an
important coordinator of behavioral and psychologicalstress in the forebrain (McKlveen et al. 2015). Additionally, these mice express high levels of the inflammatory
cytokine gene IL-12/IL23 p40 (Fig. 6). IL12/23 frommicroglia activates neurons in the mPFC to form anabnormal number of dendritic spines that may lead to thehyperactivation of neurons, potentially causing the dysregulation of neural circuits in the CNS (Abe et al. 2022;
Kaufmann and Moser 1991). Neurological pathologies
in the mPFC may explain why SDS-subjected MRL-lpr
mice show disinhibited behaviors like agitation, psychosis, and ACS. Interestingly, the enhanced expression of
IL-12/IL23 p40 in the CSF and atrophy in the mPFC areprominent in patients with dNPSLE, suggesting neuraland microglial hyperactivation like that observed in SDSsubjected MRL-lpr mice (Abe et al. 2022). Further, theadministration of IL-12R (a common receptor for IL-12
and IL-23)-blocking antibodies and tyrosine kinase-2
inhibitors reduced abnormal behaviors and dendritic
spine hyperplasia in SDS-subjected MRL/lpr mice (Abeet al. 2022). Therefore, our observations indicate a positive correlation between dNPSLE and the SDS-subjected
MRL-lpr model in an immunological and clinical pointof view. Following these findings, IL-12/IL23 p40 mainlyTanaka et al. Bioelectronic Medicine(2023) 9:24

Page 9 of 11

Fig. 6 Sleep disturbance stress (SDS)-subjected MRL/lpr mice as a model of neuropsychiatric SLE (NPSLE). Under SDS, MRL/lpr mice show
disinhibited anxiolytic behaviors. SDS induces sequential nerve activation in the paraventricular nucleus of the hypothalamus (PVN), the ventral
tegmental area (VTA) and medial prefrontal cortex (mPFC) to release IL-12/23 p40 from microglia in the mPFC. This cytokine excessively activates
brain neurons to induce the hyperplasia of dendritic spines in the mPFC. SDS-subjected MRL/lpr mice demonstrate patterns of disease symptoms
in NPSLE patients including high IL12/23 p40 production in the cerebrospinal fluid (CSF) and atrophy in the mPFC. Anti-IL12/23 p40 challenges
improve the clinical features between SDS-subjected MRL/lpr mice and human NPSLE, indicating the pathological roles of IL12/23 p40 in these
psychological disorders

released from the mPFC is a potential therapeutic target
for dNPSLE.

Conclusion
The gateway reflex describes neuro-immune interactionsat specific boundaries between the CNS and adjacent
blood vessels during inflammatory and immune events.
Several types of environmental stimulations, including
gravity, pain, psychological stress, and light, activate specific neural pathways to establish immune cell gateways
at specific blood vessels including the CNS and cause
tissue-specific inflammatory diseases. From a clinicalpoint of view, the manipulation and control of the gateway reflex are potential management strategies for someinflammatory diseases. Recent advances in techniques
for the artificial control of neural activation, such as
chemogenetics and optogenetics, may be used to activate specific neuronal projections leading to neurologicaland psychological manifestations (Roth 2016; Bernsteinand Boyden 2011), raising the possibility of manipulating brain microinflammation during the gateway reflex.
Blockade for neuropeptides or extracellular ATP binding
to their receptors in the stress gateway reflex will become
novel therapeutic strategies to prevent stress-induced
mortality or NPSLE. We expect that novel strategies
to artificially modulate the gateway reflex will provide

treatments for chronic inflammatory diseases and cancers by inhibiting or accelerating immune cell entry into
the CNS.
Acknowledgements
We appreciate the excellent technical assistances provided by Ms. M. Taru, Mr.
K. Higuchi, and Ms. C. Nakayama, and thank Ms. N. Yamamoto, Ms. Morita, and
Ms. M. Ohsawa for their excellent assistance. We thank Dr. P. Karagiannis for
carefully reading the manuscript.
Authors’ contributions
HT and MM wrote the manuscripts and figures. All authors reviewed andedited the paper. The authors read and approved the final manuscript.
Funding
This work was supported by Grant-in-aid for Scientific Research (KAKENHI)(#20H00502 and #21K19364 to M.M.), Quantum LEAP Flagship Program(JPMXS0120330644 to M.M.), Agency for Medical Research and Development(AMED) (#JP22ek0510030, #JP223fa627005 to M.M.), and AMED Moonshot(#JP21zf0127004 to M.M.), by the Grant for Joint Research Program of theInstitute for Genetic Medicine, Hokkaido University, Photo-excitonix Project,
and the Project of Young Investigator Promotion at Hokkaido University.
Availability of data and materials
Not appreciable.

Declarations
Ethics approval and consent to participate
All animal experiments were performed under the guidelines of the Institutional Animal Care and Use Committees of the Graduate School of Frontier
Biosciences and Graduate School of Medicine, Osaka University, and theInstitute for Genetic Medicine, Hokkaido University. The protocols for animal

Tanaka et al. Bioelectronic Medicine(2023) 9:24

experiments were all approved by the Institutional Animal Care and Use Committees of the Graduate School of Frontier Biosciences and Graduate School of
Medicine, Osaka University, and the Institute for Genetic Medicine, Hokkaido
University. Ethical approval for the clinical studies was granted by institutional
review board of Hokkaido University Hospital and that of Kitasato University
School of Medicine. and for the animal experiments and clinical studies was
granted by the Institutional Animal Care and Use Committees of Hokkaido
University (approval number: 14–0083). These studies are according to the
Declaration of Helsinki. Participants gave informed consent to participate in
the study before taking part.
Consent for publication
Not appreciable.
Competing interests
All authors declare they have no competing interests.
Received: 5 July 2023 Accepted: 27 September 2023

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