DOI: 10.6084/m9.figshare.29634755
title: Figure 1; Figure 2 ; Figure 3; Figure 4; Figure 5; Figure 6; Table 1; Table 2; Table 3; Table 4; Table 5

description: <b>List of Figures</b><b>Figure 1.</b> <b>Temporal dynamics of immune and inflammatory responses following traumatic brain injury (TBI): </b>Protective (green) and harmful (blue) responses from key immune cells, including M1/M2 microglia/macrophages, neutrophils, NK/dendritic/T cells, are shown over time from acute (days) to chronic (months to years) phases post-TBI. Triggered by various danger-associated molecular patterns (DAMPs), these responses lead to cytokine/chemokine signaling, glial scar formation, and either repair/regeneration or volume loss/degeneration. Dysregulated inflammation driven by persistent triggers contributes to secondary injury, neurodegeneration, and chronic pathology.<b>Figure 2. Microglial activation and chronic neuro-inflammation following traumatic brain injury (TBI): </b>TBI triggers the activation of resting microglia into M1-like (pro-inflammatory) and M2-like (anti-inflammatory) phenotypes. While a balanced M1/M2 response supports repair through phenotypic plasticity and regulated inflammation, persistent M1 dominance leads to chronic dysregulated neuro-inflammation. This state is characterized by upregulated inflammatory markers (CD68, MHC II, NOX2), elevated cytokines (CXCL8, IL-6, IL-1β, TNF), and impaired anti-inflammatory signaling (e.g., IL-10). Chronic microglial activation contributes to white matter degeneration, neurodegeneration, memory loss, dementia, and encephalopathy.<b>Figure 3. Mechanisms driving microglial polarization in traumatic brain injury (TBI): </b>Following TBI, microglia polarize into either M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes under the influence of various signals. M1 polarization is driven by TNF, IFN-γ, IL-6, reactive oxygen species (ROS), and DAMPs, and is regulated by transcriptional factors like NF-κB, STAT1, IRF-5, and miR-155. These cells produce IL-1β, TNF, and NOS2, contributing to neurodegeneration and regeneration inhibition. In contrast, M2 microglia are activated by IL-4, IL-10, and TGF-β, with regulatory pathways involving STAT3/STAT6, PPARγ, Nrf2, and miR-124. M2 cells promote neurogenesis, repair, and synaptic plasticity via anti-inflammatory cytokines and trophic factors.<b>Figure 4. Spatiotemporal dynamics of neuro-immune responses across the blood–brain barrier (BBB), blood, CSF barrier, and peripheral immune systems following TBI: </b>Traumatic brain injury (TBI) disrupts CNS barriers, triggering acute and chronic inflammatory responses. Over time, microglia shift from an M2-like to M1-like phenotype, promoting neurodegeneration. The blood, CSF and BBB undergo structural and functional changes, facilitating the infiltration of immune cells and inflammatory mediators. Key contributors include ROS, DAMPs, cytokines (IL-1, IL-18), and brain antigens. Peripheral immune components, such as lymphoid tissue, gut microbiota, and autoantibody-producing cells, further amplify neuro-inflammation. Modulatory interventions (e.g., PPAR agonists, chemokine antagonists, immunoglobulin therapy, rehabilitation, and gut microbiota regulation) offer potential for long-term neuroprotection.<b>Figure 5. Bidirectional communication between the gut and brain via the gut–brain axis under stress and dysbiosis</b>: Diet, stress, and microbial imbalance alter gut microbiota composition and increase intestinal permeability ("leaky gut"), allowing microbial components to trigger immune responses. These responses involve cytokine release (TNF-α, IL-6, IFN-γ), hormonal signaling (PYY, CCK, 5-HT), and microbial metabolites (SCFAs, GABA, 5-HT precursors), which influence brain function via the vagus nerve and spinal pathways. Conversely, brain-derived signals, particularly stress-induced cortisol, disrupt gut barrier integrity and microbiota homeostasis. This bidirectional pathway plays a crucial role in modulating inflammation, neuroendocrine activity, and behavioral responses.<b>Figure 6. Stress-induced hypothalamic pituitary adrenal (HPA) axis activation and its impact on microglial programming across developmental stages.</b>Psychological or physiological stress activates the HPA axis, leading to glucocorticoid release from the adrenal glands. These hormones affect the hippocampus, amygdala, and hypothalamus, altering neuronal and glial signaling. Microglia, in response to repeated stress, undergo epigenetic and transcriptional reprogramming toward a pro-inflammatory phenotype. This maladaptive microglial activation disrupts neurogenesis and synaptic remodeling, increasing neuroinflammatory cytokine release. The magnitude and vulnerability of these effects vary with developmental stage—greatest during early life, adolescence, and aging, highlighting critical windows for stress-induced neuroinflammation and disease risk.<b>List of Tables</b><b>Table 1. Inflammatory biomarkers and mediators in traumatic brain injury: Sources, dynamics, and associations with clinical outcomes. </b>This table summarizes key cell-based mediators (e.g., microglia, astrocytes) and molecular triggers (e.g., mitochondrial DNA, glutamate, HMGB1) involved in TBI-associated inflammation. It highlights their origin (tissue or fluid), temporal profiles, and links to clinical outcomes such as white matter degeneration, elevated intracranial pressure, and poor Glasgow Outcome Scale (GOS) scores. The observations underscore the complex time-dependent pathophysiology of TBI and the potential of these markers in prognostic or therapeutic applications.<b>Table 2. Cytokines and chemokines in cerebrospinal fluid, extracellular fluid, and tissue following traumatic brain injury: Temporal profiles and clinical relevance</b>: This table summarizes the expression patterns of key inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-10, TNF, CCL2, CXCL8, and GM-CSF, following traumatic brain injury (TBI). It highlights their source (CSF, ECF, or brain tissue), associations with clinical outcomes (e.g., mortality, GOS score, intracranial pressure), and the timing of their peak expression. The observations emphasize their utility in stratifying patient risk and understanding injury phase-specific immune dynamics.<b>Table 3. Clinical trials of inflammation-modulating therapies in traumatic brain injury: Efficacy, inflammatory targets, and study limitations:</b> This table summarizes randomized controlled trials (RCTs) evaluating pharmacological agents, including dexanabinol, G-CSF, cyclosporin A, erythropoietin, and anatibant, for their effects on inflammatory pathways following TBI. It presents therapeutic doses, primary and secondary clinical outcomes, anti-inflammatory mechanisms (e.g., TNF inhibition, cytokine modulation), and trial-specific observations. Despite promising mechanistic targets, most interventions failed to improve functional outcomes (e.g., GOS-E scores), highlighting the complexity of immune modulation in TBI and the need for more targeted, stratified therapeutic approaches.<b>Table 4. Clinical evaluation of non-conventional and adjunctive therapies targeting neuroinflammation in traumatic brain injury</b>: This table summarizes the outcomes of clinical trials assessing probiotics, hypertonic saline, anakinra (IL-1 receptor antagonist), and therapeutic hypothermia in patients with moderate to severe TBI. It outlines dosage, study design, primary and secondary outcomes, mechanistic effects on inflammation (e.g., cytokine modulation, T-cell function, microglial polarization), and notable safety or efficacy concerns. Despite promising immune-modulatory effects, most trials showed no significant improvement in clinical endpoints, emphasizing the challenges in translating immunotherapies to effective TBI treatments.<b>Table 5. Clinical outcomes of steroidal and statin-based interventions targeting neuroinflammation in traumatic brain injury:</b> The randomized controlled trials assessing corticosteroids (methylprednisolone, dexamethasone, hydrocortisone, and progesterone) and statins (rosuvastatin) for their immunomodulatory effects in TBI patients. It includes therapeutic doses, study design, primary and secondary clinical outcomes, and their effects on inflammation (e.g., cytokine suppression, leukocyte inhibition, and microglial regulation). Despite theoretical benefits such as reduced IL-1β, TNF, and leukocyte infiltration, most trials failed to show efficacy or raised safety concerns, especially with high-dose steroids, highlighting the complexity of inflammation targeting in TBI.<br>