Addictive drugs impact corticostriatal glutamate signaling and have immunomodulatory effects which may underlie drug-associated behaviors during different phases of the addiction cycle. Here we hypothesize that glutamate dyshomeostasis induced by addictive drug use and withdrawal is heavily orchestrated by the neuroimmune system. We systematically define how drug-induced pathologies within the nucleus accumbens (NA) glutamate tripartite synapse are tightly regulated by neuroimmune signaling. Targets within the neuroimmune system represent a novel approach that can be leveraged for clinical studies with immunomodulatory therapeutics to reverse neurobiological changes induced by addictive drugs, and thus meaningfully reduce negative clinical outcomes relevant to substance use disorders (SUDs). We outline a novel hypothesis that control of a newly defined neuroimmune-glutamate circuit and inflammasome is heavily dependent upon the type of addictive drug as well as on phase of the addiction cycle. We further provide translational evidence underscoring the tenet that neuroimmunomodulation by addictive drugs functions according to an opponent process, and we outline predictions of our opponent process hypothesis when applied to relevant polysubstance use patterns in people who use drugs. This framework could be strategically leveraged in the experimental design of clinical studies of novel SUD therapeutics.
PANoptosis, a collective form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, is turning out to be a key player in the neuroimmune activation and sustaining chronic neuroinflammation in the nervous system. PANoptosis, in contrast to single cell death mechanisms, is a web of events coordinating neuronal death, glial cell changes, and inflammatory signals, being implicated in the initiation and progression of neurodegenerative and neuroinflammatory diseases. This review compiles current knowledge of the molecular pathways of PANoptotic signaling, its interaction with autophagy and immune pathways, and the in vivo models utilized for its pathogenic role in the central nervous system. We also tackle translational hurdles such as biomarker identification, therapeutic safety, disease, stage precision, and patient heterogeneity, which all point to the necessity of highly accurate interventions. Moreover, novel techniques combining systems biology, AI-based target identification, and personalized neuroimmunomodulation may effectively harness PANoptosis regulation to be both controlled and disease-specific. Through bridging the gap between the mechanistic insights and the translational perspectives, this review points out that PANoptosis provides a comprehensive basis for neuroimmune-associated pathology and represents a viable target for novel therapeutic approaches to counteract both chronic neuroinflammation and neurodegeneration.
Diabetic wounds are a severe complication of diabetes, which can lead to amputation or even mortality in severe cases. While normal wound healing consists of four phases: hemostasis, inflammation, proliferation, and remodeling, diabetic wounds tend to become chronic and refractory primarily due to a prolonged inflammatory phase. In diabetic wounds, insufficient synthesis and release of endogenous calcitonin gene-related peptide (CGRP) is a critical upstream mechanism underlying the disrupted neuro-immune communication, the persistent inflammation, and the arrested wound healing process. In contrast to pure skin defect wounds, where CGRP is rapidly upregulated after injury, CGRP remains persistently low in diabetic wound tissue, consequently failing to drive macrophage polarization towards the M2 phenotype or promote vascular maturation and collagen fiber deposition in the later phase of inflammation. In the early inflammatory phase, CGRP exerts pro-inflammatory effects by enhancing angiogenesis and modulating macrophage polarization. In the late inflammatory phase, CGRP upregulates thrombospondin-1, promotes neutrophil apoptosis and phagocytic clearance, thereby inhibiting excessive inflammatory response and shifting the wound microenvironment from a pro-inflammatory state to a pro-reparative state. Restoring CGRP signaling reconstructs the neuroimmunomodulation axis and improves wound repair while relieving diabetic neuropathic pain. Engineered CGRP combined with intelligent delivery systems offers promising prospects for diabetic wound therapy. However, large-scale clinical trials are still required to validate its clinical efficacy and safety. This paper systematically analyzes the mechanisms and application strategies of CGRP in facilitating diabetic wound repair, which can provide a theoretical basis and innovative strategies for clinical management. 糖尿病创面是一种糖尿病并发症，严重者可致患者截肢甚至死亡。正常的创面愈合历经止血、炎症、增殖、重塑4个阶段，糖尿病创面主要因炎症期延长而慢性难愈。糖尿病创面组织中降钙素基因相关肽（CGRP）合成与释放不足，这是导致创面神经免疫通讯中断、炎症无法消退、愈合进程停滞的关键上游机制。与单纯皮肤缺损创面中CGRP在伤后迅速上调不同，糖尿病创面组织中CGRP呈持续性低水平表达，无法在炎症后期驱动巨噬细胞向M2型极化，促进血管成熟与胶原纤维沉积。在炎症初期，CGRP通过促进新血管生成、调节巨噬细胞极化等发挥促炎作用；而在炎症后期，CGRP通过上调血小板反应蛋白-1，促进中性粒细胞凋亡与胞葬清除，进而抑制过度炎症反应，推动创面微环境由促炎状态向促修复状态转变。恢复CGRP信号可重塑神经免疫调控轴，兼具促进创面修复与缓解糖尿病神经病理性疼痛的双重作用。工程化CGRP与智能递送系统为糖尿病创面治疗带来新希望，但其在临床应用中的有效性与安全性仍需大规模研究验证。该文深入剖析CGRP在糖尿病创面修复中的作用机制及应用策略，为临床治疗提供理论依据与新思路。.
The cholinergic anti-inflammatory pathway (CAP) plays a central role in neuroimmunomodulation, and its activation is a potential strategy for ameliorating sepsis-associated acute kidney injury (SA-AKI). However, further investigations are necessary to understand the molecular mechanisms of CAP activation and develop therapies for SA-AKI. Here, we tested whether the Notch signaling pathway, which regulates cell-cell interactions, mediates the anti-inflammatory effects of CAP. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we found that CAP activation by vagus nerve stimulation (VNS) enhanced Notch2 signaling in macrophages, mitigating inflammation in the spleen and tissue damage in the kidneys. Consistently, macrophage-specific knockout of Notch2 resulted in an attenuation of these anti-inflammatory effects of VNS. We also demonstrated that VNS and macrophage-specific Notch2 signaling might upregulate transferrin, which maintains iron homeostasis, thereby protecting the kidneys. Taken together, our findings suggest the involvement of Notch signaling in the mechanisms of VNS-mediated CAP activation during LPS-induced AKI.
Background the deployment of fifth-generation (5G) wireless telecommunications infrastructure, incorporating millimeter-wave (mmWave, 24-100 GHz) and sub-6 GHz frequencies, has renewed scientific and public health interest in the potential neurobiological effects of radiofrequency electromagnetic fields (RF-EMF). While extensive research has examined lower-frequency RF-EMF from 2G/3G/4G technologies, the specific effects of mmWave frequencies on CNS cellular biology-including microglial polarization and intracellular calcium signaling-remain less characterized. This systematic review evaluates experimental evidence from in vitro and in vivo studies on the effects of high-frequency EMF (300 MHz-300 GHz) on neuroimmune responses, microglial function, CNS calcium homeostasis, and related outcomes. Methods PubMed, EMBASE, Web of Science, and the EMF-Portal were searched from inception to January 2026 following PRISMA 2020 guidelines. Experimental (in vitro and animal) studies reporting CNS-relevant outcomes after high-frequency RF-EMF exposure were eligible. Exposure must have been within the 300 MHz to 300 GHz range. Quality assessment used adapted OHAT risk-of-bias criteria. A narrative synthesis was conducted; quantitative pooling was performed where three or more studies reported the same outcome. Results forty-one studies met inclusion criteria (see PRISMA Flow Diagram, Fig. 1): 7 in vitro (cell culture), 29 in vivo (rodent model), and 5 reviews/meta-analyses. The detailed characteristics of all included studies are summarized in Table 1. At specific absorption rate (SAR) levels at or below the International Commission on Non-Ionizing Radiation Protection (ICNIRP) general public exposure guidelines (2 W/kg averaged over 10 g), the majority of studies (27/41, 66%) found no statistically significant effects on neuroinflammatory markers, microglial morphology, or calcium signaling. Eleven studies (27%) reported transient, low-magnitude increases in intracellular Ca²⁺ or pro-inflammatory cytokine expression at exposures near or exceeding guideline limits; these effects were not consistently reproducible across independent laboratories. Three studies (7%) reported effects below guideline thresholds that may warrant further investigation. No study identified neuropathological changes (neuronal death, axonal injury) attributable to RF-EMF at guideline-compliant exposures. Conclusions current experimental evidence does not establish that high-frequency RF-EMF at guideline-compliant exposure levels produces significant adverse effects on microglial polarization, CNS calcium homeostasis, or neuroinflammatory responses. Methodological heterogeneity, inadequate dosimetry, and limited independent replication constrain confidence in both positive and negative findings. Standardized, rigorously controlled experimental studies are needed, particularly for mmWave frequencies (> 6 GHz) where data are sparse. Our findings support the current scientific consensus that high-frequency RF-EMF below regulatory limits does not pose a clearly established neurobiological hazard. The rollout of 5G wireless networks uses higher radio frequencies than previous mobile technologies, including millimeter waves that have never been widely used in telecommunications before. Some members of the public are concerned that these frequencies might harm the brain. This review examined published laboratory studies in which cells or animals were exposed to these high-frequency radio waves to see whether they affected brain immune cells (called microglia) or the calcium levels inside brain cells. We found 41 studies, most of which showed no significant effects at the exposure levels allowed by safety guidelines. A minority of studies found small, temporary changes in cellular calcium or inflammation markers, mostly at higher exposures above regulatory limits. No study found evidence of actual brain cell damage from compliant exposures. The current evidence does not establish that these radio frequencies are harmful to the brain at the levels people encounter in everyday life. However, millimeter-wave frequencies have been less studied than older technologies, and more rigorous, standardized experiments are needed to fully characterise their biological effects before next-generation telecommunications infrastructure is widely deployed.
Balneotherapy is a potential complementary approach for sleep problems, but its short-term sleep effects and accompanying biological changes remain unclear. We conducted a prospective single-arm, self-controlled pilot study of 30 adults with sleep disorders, who completed a 10-day residential hot spring balneotherapy program (twice daily at 09:00 and 20:00, 30 min per session, 40-42 °C) at Tianhe Hot Spring, Sichuan Province, residing on-site and receiving identical meals throughout the intervention. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and wrist-worn wearable tracking. Serum neurotransmitters, inflammatory cytokines and tryptophan-kynurenine metabolites were assayed, while 16 S rRNA-based gut microbiota profiles were profiled pre- and post-intervention. Post-intervention, PSQI scores decreased, while wearable metrics indicated longer total and nocturnal sleep duration, elevated deep-sleep duration and proportion, better sleep continuity, and a lower rapid eye movement (REM) percentage (P < 0.05). Blood pressure, anxiety/depression scores, and wearable-derived sleep-stress indices also improved. Biomarker profiling revealed elevated GABA, 5-HT, 5-HIAA, BDNF, and IL-10, alongside reduced IL-1β, IL-6, and TNF-α (P < 0.05). Trp metabolism shifted, characterized by decreased Trp and increased 3-HAA and PA (P < 0.05). Structurally, the gut microbiota exhibited an increased abundance of Blautia_A (P < 0.05), with LEfSe analysis identifying post-intervention enrichment of Turicibacter and pre-intervention predominance of Agathobacter. Cross-system network analysis further established 5-HT, IL-6, and IL-10 as the core candidate biomarker profile directly correlating with these multi-domain sleep improvements. Overall, short-term residential hot spring balneotherapy may improve subjective and wearable-derived sleep outcomes, accompanied by coordinated cardiovascular, stress-related, neuroimmune, tryptophan-metabolic, and gut microbiome changes, supporting a multi-system physiological basis for balneotherapy-related sleep improvement.
The pathogenesis of atherosclerosis has progressively shifted from a lipid-centric model to one that recognizes inflammation as the central driver. Smoking is a well-established chronic risk factor, whereas acute infections are increasingly recognized as transient triggers of acute cardiovascular events. This review synthesizes the distinct yet overlapping mechanisms by which chronic smoking and acute infections contribute to atherogenesis and plaque destabilization within an integrated neuroimmune framework. This narrative review was developed using AI-assisted literature search tools (ChatGPT, OpenAI; Claude, Anthropic) to identify relevant publications from 1990 to 2025. All references were independently verified using PubMed and original source links. Selection prioritized mechanistic studies addressing inflammatory pathways, endothelial dysfunction, and immune modulation. Smoking promotes atherogenesis through sustained endothelial injury, lipoprotein oxidation, chronic sympathetic activation, and hematopoietic reprogramming, favoring proinflammatory monocyte mobilization. Infections elicit acute cytokine surges, sympathetic-mediated macrophage activation, and prothrombotic cascades that destabilize preexisting plaques. Smoking contributes to plaque initiation and growth, whereas infections primarily act as event triggers. Atherosclerosis emerges from chronic and episodic inflammatory processes with distinct temporal profiles. Smoking is a continuous driver of plaque formation, whereas acute infections promote plaque destabilization. Future research should examine their interplay, particularly in smokers exposed to recurrent or low-grade infectious states.
The neuroimmune system, an extensive bidirectional communication system between neural cells and immune cells, utilizes evolutionarily conserved molecules, including cytokines, chemokines and trophic factors that participate as mediators in both directions. While the initial discovery of classic immune molecules in the brain was interpreted as neuroinflammation, a broad literature demonstrates their essential roles in cognition during homeostatic brain function. These mechanisms include neural correlates of learning and memory, such as strengthening of neuronal networks and the generation of new neurons and synaptic connections. These processes take place throughout the brain, especially in the hippocampus, a major component of the brain of humans and other vertebrates that consolidates short-term memory into long-term memory and supports spatial navigation. This Review explores recent developments and understanding of immune molecules that orchestrate and participate in molecular mechanisms of memory formation. It also considers their potential efficacy as new targets to treat memory disorders.
Autism spectrum disorder manifests through dysbiosis across the microbiota-gut-brain-immune axis, characterized by depletion of short-chain fatty acid (SCFA)-producing taxa like Bifidobacterium, Faecalibacterium, and Roseburia, along with an increase in endotoxin-producing taxa like Desulfovibrio and Bacteroides. SCFA emerge as one of the regulators of neuroimmune homeostasis by governing microglial maturation through GPR43/GPR109A-dependent histone deacetylase inhibition, modulating astrocytic tryptophan-aryl hydrocarbon receptor signaling, and preserving tight junction integrity at blood-brain and blood-CSF barriers. SCFA insufficiency constitutes the upstream metabolic defect linking gut dysbiosis to ASD neuropathology, such as impaired microglial priming and brain-resident CD4+ T cell differentiation, reactive astrocytosis with kynurenine neurotoxicity superseding protective signaling, barrier breakdown enabling LPS-driven TLR4-NF-κB neuroinflammation, and excitatory/inhibitory imbalance from reduced glutamate decarboxylase and astrocyte glutamate dysregulation. This review advances an integrative SCFA-centric framework repositioning ASD as metabolite-dependent neuroimmune dysregulation during brain development. Preclinical and early clinical data demonstrate that SCFA restoration through prebiotic fiber/resistant starch, probiotics, or direct SCFA supplementation normalizes gastrointestinal symptoms, behavioral deficits, microglial morphology, and neurotransmitter ratios. This guides mechanistically targeted microbiota interventions with fecal/plasma SCFA profiling as stratification biomarkers, establishing precision therapeutic regimens for ASD.
The Leptospira-associated acute encephalopathy syndrome (AES) is a severe neurological complication, largely affecting the endemic regions. Unlike other classical neurotropic infections, Leptospira-induced encephalopathy is mainly induced via immune-mediated mechanisms through dysregulation of glial response and peripheral immunity. The onset of infection is marked by the invasion of early innate immune clearance. There is a substantial presence of bacteremia and elevated peripheral inflammation due to the atypical engagement of pattern recognition receptors. The enhanced circulating cytokines and endothelial dysfunction cause blood-brain barrier disruption, along with the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) cascades. The subpopulations of the glial cells are the primary central nervous system (CNS) populations that undergo activation, such as microglia and astrocytes, to re-establish homeostasis. There is a positive feedback loop activation for the inflammation pathway, with exacerbated cerebral edema and neuronal dysfunction, which are characteristic of AES. The severity of neuronal parasitic disease correlated with immune dysregulation and glial activation rather than the direct Leptospira infection in the neuronal tissue. It may be proposed that the Leptospira-induced AES represents a neuroimmune disorder in which peripheral immune activation and glial-driven neuroinflammation converge to produce acute cerebral dysfunction. Understanding these interconnected pathways is essential for improving diagnosis and developing targeted therapeutic strategies for Leptospirosis/Leptospira-associated AES.
The cochlear aqueduct, located within the temporal bone, forms a narrow connection between the cerebrospinal fluid (CSF) in the subarachnoid space and the perilymph of the scala tympani in the inner ear. The anatomical linkage provides a potential interface for pressure regulation, molecular exchange, and therapeutic access to the cochlea. Recent findings further indicate that the cochlear aqueduct is functionally coupled to the brain's glymphatic system, permitting CSF flow to the inner ear and raising the possibility of an inner ear glymphatic system. Morphological studies demonstrate substantial interspecies variability in cochlear aqueduct size and patency among species, and identified a diaphragm-like terminal membrane at its lateral end. In mice, immunocytochemical analyses indicate a lymphatic-like phenotype reminiscent of the subarachnoid lymphatic-like membrane (SLYM). The presence of macrophages with phagocytic capacity and the fact that the membrane is activated during bacterial meningitis further supports a role in local immune surveillance. The translational relevance of the cochlear aqueduct has gained attention with advances in inner-ear gene therapy. Tracers injected in cisterna magna in mice reach the inner ear rapidly. In rodents and non-human primates, intracisternal injection of viral vectors via achieves efficient bilateral cochlear transduction, including restoration of hearing in VGLUT3-deficient mice, a model of nonsyndromic deafness. These findings position the cochlear as a minimally invasive route for inner-ear therapy, potentially avoiding direct cochlear surgery. However, interspecies differences and age-related changes in cochlear aqueduct patency must be carefully evaluated before clinical translation.
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune dysregulation across the lifespan. Accumulating evidence suggests that many immunological alterations observed in SLE resemble those seen in physiological aging. Here, we review the major innate and adaptive mechanisms of immunosenescence in SLE, including telomere shortening, chronic low-grade inflammation, thymic dysfunction, and the expansion of senescent immune cell subsets. Of note, we discuss how these age-associated immune phenotypes emerge early and contribute to disease activity, organ damage, and long-term outcomes. Clinically, immunosenescence contributes to cardiovascular complications, frailty, increased infections, and cognitive impairment in SLE. Therapies targeting senescence-related pathways - including modulation of intracellular metabolic pathways and senolytics - are also discussed and constitute promise as emerging strategies.
Numerous central nervous system pathological conditions involve blood-brain barrier (BBB) disruption and the egress of immune cells in the brain. Controlling immune cell transmigration into the brain represents a potential therapeutic target. This study describes the application of a 3D human BBB spheroidal model that consists of six major brain cell types to test the transmigration of immune cells under normal and pathological conditions of inflammation and ischemia-reperfusion injury (IRI). The cell types in the BBB organoid include brain microvascular endothelial cells (HBMVECs) and pericytes at the spheroids' surface, surrounding a core of astrocytes, microglia, oligodendrocytes, and neural progenitor cells. The model recapitulates the interaction of CD4+ T-cells and immunomodulators with HBMVECs at the BBB including changes in cell adhesion molecules expressed on their surface. This study demonstrated that the human 3D BBB model recapitulates many features of the barrier under normal and pathological conditions of inflammation and hypoxia-reperfusion injury. Proinflammatory cytokines and hypoxia disrupt the barrier and increase its permeability, decreasing the expression of tight junctions. Proinflammatory cytokines and reperfusion increase the expression of cell adhesion molecules and increase immune cell transmigration. Immune cell transmigration could be reduced with anti-cell adhesion molecule antibodies, further validating the model for studying neuroimmune interactions and for conducting high-throughput screening of therapeutic targets that modulate immune cell transmigration into the brain.
The major histocompatibility complex class II (MHC-II) pathway is central to adaptive immunity and immune tolerance, and its age-related dysregulation is increasingly linked to chronic neuroinflammation. The HLA-DRB1*15:01 allele, the strongest genetic risk factor for multiple sclerosis, has been implicated in shaping pathogenic CD4+ T-cell responses and broader neuroimmune vulnerability, yet how this allele modulates age- and sex-dependent neuroimmune processes within the central nervous system (CNS) remains poorly defined. We investigated the impact of HLA-DRB1*15:01 expression using a humanized mouse model (HLA mice) and wild-type (WT) controls. Male and female mice were analyzed at 6, 9, and 15 months of age, with endocrine stratification in females. Behavioral testing, flow cytometry, immunofluorescence, and multiplex cytokine analyses were used to assess cognitive performance, glial immune-associated changes and oxidative stress, astrocyte-microglia IL-3/IL-3R signaling, endothelial activation, selective immune cell accumulation at CNS borders, tissue organization, and hippocampal cytokine profiles. HLA mice developed age- and sex-dependent cognitive impairment, most pronounced in aged females. HLA-DRB1*15:01 expression promoted progressive microglial immune-associated changes, characterized by increased CD14 and CD68 expression, elevated mitochondrial oxidative stress, altered astrocyte phenotypes, and enhanced IL-3/IL-3R signaling. Hippocampal axonal and myelin organization was disrupted in aged HLA mice and was spatially associated with increased microglial presence. HLA mice also exhibited selective immune remodeling, including increased accumulation of CD4+ T cells and NK1.1+CD3+ natural killer T (NKT) cells, particularly in females, accompanied by endothelial activation marked by elevated ICAM-1 and E-selectin expression. Hippocampal cytokine profiling revealed selective sex-biased alterations, without broad induction of classical inflammatory cytokines. Together, these findings demonstrate that HLA-DRB1*15:01 drives a coordinated, age- and sex-dependent neuroinflammatory program linking behavioral dysfunction, glial immune-associated changes and oxidative stress, selective immune cell recruitment, endothelial activation, tissue remodeling, and targeted cytokine imbalance. This integrated phenotype provides mechanistic insight into how this major MS risk allele confers vulnerability to chronic neuroinflammation during aging, with heightened impact in females, independent of reproductive cycling stage.
Brazil ranks second globally in leprosy burden, with approximately 25 000 cases reported in 2022. This study aimed to analyse the 26-year experience (1997-2023) in nerve biopsies at a specialized leprosy outpatient clinic, focusing on their usefulness in diagnosing peripheral neuropathy in patients with clinical and neurophysiological features suggestive of leprosy but lacking dermatological lesions. Tissue samples were preserved in glutaraldehyde, buffered formalin and liquid nitrogen, with histopathological analysis using various staining techniques and molecular testing on frozen material. In 819 cases, 529 were diagnosed with leprosy (64.6% overall leprosy diagnosis rate), and 207 pure neural leprosy cases were confirmed. Other conditions identified included vasculitis, diabetic neuropathy and amyloidosis, while 16.5% of cases yielded inconclusive results. The predominant clinical symptoms included sensory disorders (85.7%), localized paraesthesia (70.3%) and muscle weakness (59.4%), with multiple mononeuropathies frequently observed on electroneuromyography. The most biopsied nerves were the ulnar cutaneous branch (50.6%), sural (37.2%) and superficial peroneal (6.8%). Nerve biopsy proved valuable for confirming leprosy and distinguishing differential diagnoses in complex cases, particularly when clinical findings alone were insufficient. Integrating clinical-pathological correlation optimized diagnostic accuracy, underscoring the importance of this tool in managing suspected neural leprosy and guiding treatment in challenging cases.
Barrier tissues-including the skin, respiratory tract, and gastrointestinal tract-are dynamic interfaces where neural and immune systems converge to coordinate barrier defense, inflammation, and repair. Recent studies show that neurons and immune cells form bidirectional networks that sense environmental cues, pathogen-derived signals, and tissue stress to fine-tune immunity and maintain homeostasis. Sensory, sympathetic, parasympathetic, and enteric neuronal pathways shape epithelial function, vascular dynamics, and immune activation across barrier tissues. Through neurotransmitters and neuropeptides, neuroimmune circuits regulate pathogen clearance, preserve tissue integrity during infection, modulate allergic and autoimmune responses in sterile inflammation, and support tissue regeneration by instructing immune cell reprogramming and epithelial renewal. Together, these findings establish neuroimmune communication as a key regulatory layer of barrier tissue physiology and reveal therapeutic opportunities to restore immune balance and promote barrier resilience through targeted neuromodulation and immunomodulation.
Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation.
Functional constipation (FC), particularly slow-transit constipation (STC), is a heterogeneous disorder of gut-brain interaction that responds poorly to conventional therapies. Accumulating evidence links the microbiota, mucosal immunity, and the enteric nervous system (ENS); their mechanistic integration remains incomplete. In this narrative review, we propose a Trigger-Gateway-Hub-Effector framework as a heuristic and hypothesis-generating model to organize fragmented evidence on microbial-to-immune-neural interactions. Within this framework, dysbiosis-associated microbial metabolites, including short-chain fatty acids, bile acids, methane-related pathways, and lipopolysaccharide, are considered potential upstream "Triggers" that may modulate epithelial and immune homeostasis. "Gateway" processes refer to epithelial barrier vulnerability and mucosal immune changes that may permit microbial or inflammatory signals to affect deeper intestinal compartments. At the "Hub" level, interactions among muscularis macrophages, mast cells, enteric glia cells, and neurons are proposed to integrate these signals and contribute to ENS-adjacent neuroimmune stress. These processes may converge on downstream "Effector" alterations, including neuronal vulnerability, maladaptive plasticity, and disruption of the interstitial cells of Cajal network, particularly in severe or refractory STC. However, there is currently limited direct evidence to support a continuous causal chain linking microbiome-derived signals to dysfunction of the enteroneural system. Many of the proposed mechanisms are inferred from preclinical studies or related gastrointestinal disorders. Therefore, this framework should be interpreted as a testable conceptual model rather than a confirmed pathogenic sequence. We further discuss the translational implications from a systems biology perspective, emphasizing evidence-weighted therapeutic interpretation, mechanism-guided stratification, and integrated microbial-immune-ENS assessment. Future human-centered studies combining multi-omic profiling, spatial tissue analysis, and objective neuromuscular readouts are needed to refine this model and inform precision-oriented therapeutic strategies for FC/STC.
Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.
Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.