Neuroimmune Signaling Research Articles

Antibody Receptor Signaling from Spinal Cord Astrocytes Promotes Neuropathic Pain

Injury to somatosensory nerves can lead to mechanical allodynia, in which normally innocuous touch is perceived as painful. Inflammatory signaling arising from spinal cord glial cells are thought to promote allodynia, but it is unclear what mechanisms control glial activation after injury. Here we demonstrate that Fc gamma receptor IIa (FcγRIIa), an immune receptor for immunoglobulin G (IgG) antibodies, is expressed by astrocytes in the spinal cord and contributes to the development of mechanical allodynia after neuropathic injury. Neuropathic pain in male and female rats was induced by chronic constriction injury (CCI) of the sciatic nerve. Paw withdrawal to innocuous touch was measured by von Frey filaments and paintbrush assay. Intrathecal injections of IgG immune complex (IgG-IC) were used to activate spinal FcγRs. Viral-mediated CRISPR-Cas9 gene editing was used to disrupt Fcgr2a expression in Gfap+ spinal astrocytes in vivo. Gene and protein expression were measured by in situ hybridization, qRT-PCR, and immunohistochemistry. For in vitro experiments, astrocytes were purified by immunopanning and treated with IgG-IC. Activating FcγRs by spinal administration of IgG-IC produces mechanical allodynia. Fcgr2a RNA expression increases specifically in ipsilateral spinal dorsal horn after CCI, and FcγRIIa protein co-localizes primarily with GFAP+ astrocytes. Genetic disruption of Fcgr2a in Gfap+ spinal astrocytes attenuates mechanical allodynia after CCI. Astrocytes respond to IgG-IC by increasing production of pro-inflammatory mediators, including TNF and IL-1β, which are known to influence nociceptor activity. These data suggest FcγRIIa on spinal astrocytes may be activated following peripheral nerve injury and directly contribute to injury-induced tactile pain. These findings expand our understanding of how neuroimmune signaling from glia contribute to the development of mechanical allodynia and suggest that reducing autoantibody IgG signaling at glial FcγRs could be a novel therapeutic target to alleviate suffering from neuropathic pain. Grant support from U.S. Army Medical Research and Materiel Command grants W81XWH-19-1-0160 and W81XWH-16-1-0717 (PMG) Rita Allen Foundation Award in Pain (PMG) University of Texas System Rising STARs Award (PMG) University of Texas MD Anderson Cancer Center start-up funds (PMG) American Australian Association Sir Keith Murdoch Fellowship (MJL).

Vagus Nerve Sensory Neurons Respond Distinctly to Specific Inflammatory Mediators

The peripheral nervous system communicates with the immune system in response to injury or infection. In the case of inflammation, sensory signals travel up to the brain via the vagus nerve, which is a major pathway for neuro‐immune communication. While previous work from our group showed that cytokines administered systemically were associated with specific patterns of vagus nerve activity, we did not know how individual vagal sensory neurons encoded this immune information.Here, we use in vivo calcium imaging to monitor the neural activity of individual vagal sensory neurons in response to specific inflammatory mediators. Using mice that express the calcium sensor GCaMP6f in glutamatergic neurons, we imaged neurons of the nodose ganglion in situ using a 1‐photon miniature microscope (Miniscope). During imaging, the inflammatory mediators tumor necrosis factor (TNF) and interleukin 1β (IL‐1β) were applied directly to the vagus nerve. The raw fluorescence data was analyzed with a Python‐based calcium imaging analysis (CaImAn) software and a customized pipelines to output the neural activity (change in fluorescence: ∆F) of individually detected neurons. An average of 69±16.3 neurons were recorded per 1 hour imaging session.Our results reveal that specific vagal sensory neurons respond to differentially to specific immune mediators. The average amplitude, integral, and delay of TNF‐responsive neurons was significantly higher than IL‐1β‐responsive cells (TNF vs IL‐1β, p < 0.01). This result suggests that TNF application triggers responses later and with higher firing rates in responsive neurons compared to IL‐1β. Neuronal responses to IL‐1β had a significantly higher number of peaks when compared to TNF responses (IL‐1β vs TNF, p < 0.05). When compared to responses for the TRPV1‐specific agonist capsaicin, the cytokine responses were found to have significantly lower number of peaks (capsaicin vs IL‐1β, p < 0.05), which suggests that immune mediators produce different neural activity than canonical activators. Taken together, our findings demonstrate that individual vagal sensory neurons encode information about distinct inflammatory stimuli and provide insight into the neural sensing of inflammation. Further investigation into this type of neuro‐immune signaling may identify novel neural targets for the treatment of inflammatory disorders.

Vagus nerve sensory neurons have distinct neural responses to inflammatory mediators

Abstract Cytokines are secreted signaling proteins that are important mediators of inflammation. While prior work has demonstrated that the level of cytokines can be regulated by nerve stimulation, the role of the nervous system in sensing these immune mediators is still poorly understood. During periods of inflammation, it has been shown that sensory signals travel up the vagus nerve to the brain. However, it is unclear how individual vagal sensory neurons encode specific immune information. Here we use in vivo calcium imaging of the nodose ganglion to monitor neural activity in individual vagus nerve sensory neurons in response to specific cytokines. Using mice that express the calcium indicator GCaMP6f in glutamatergic neurons, we imaged neurons of the nodose ganglion in situ using a 1-photon miniature microscope (Miniscope). During imaging, the proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor (TNF) were applied directly to the vagus nerve. Fluorescence data was analyzed with a Python-based software CaImAn and a custom pipeline to output the single neuron activity as change in fluorescence: ΔF/F. Our results reveal that specific vagal sensory neurons respond differentially to specific immune mediators. The average amplitude, integral, and delay of TNF-responsive neurons was significantly higher than IL-1β-responsive cells (TNF vs IL-1β, p < 0.01), while having less number of peaks per response (TNF vs IL-1β, p < 0.05). This may suggest different patterns of transient neural activity associated with each particular cytokine. Further investigation into this type of neuro-immune signaling may identify novel neural targets for the treatment of inflammatory disorders. This study was funded in part by NIH/NIGMS

Immune Cell Regulation by Macrophage Derived Small Extracellular Vesicles in Pain

BackgroundDevelopment of chronic pain is related to aberrant neuroimmune signaling. Small extracellular vesicles (sEVs) are 30‐150nm size particles of endosomal origin. They play an important role in neuroimmune crosstalk facilitating transfer of biomolecular cargo between cells. Our studies show that sEVs from RAW 264.7 macrophage cells can be therapeutic or prophylactic in mouse model of inflammatory pain. We investigated the mechanistic basis of how sEVs from lipopolysaccharide (LPS) stimulated (Exo+) and unstimulated (Exo‐) cells impact primary glial cells, dendritic cells (DCs) and adaptive immune cells such as CD4+T cells. We hypothesize that macrophage derived sEVs can potentiate T cell activation directly, or indirectly by the upregulation of major histocompatibility complex‐II (MHC‐II) and co‐stimulatory molecules on DCs, attenuating pain hypersensitivity. We will also test if sEVs confer protection to glial cells in the context of inflammation.MethodsPrimary mouse DCs, microglia and astrocytes were incubated with 1µg Exo‐/+sEVs for 24 hours. Splenocyte derived CD4+ T cells were treated with 0.1ug Exo‐/+ sEVs for 72 hours. Flow cytometry and qPCR was used for analysis.ResultsCharacterization of RAW sEVs showed the presence of sEV markers CD81 and Alix. sEV treatment of DCs resulted in an increase in CD80+/CD86+ MHCIIhiCD11c+/hi DCs. Treatment of CD4+T cells with sEVs increased Tgf‐βexpression. Pretreatment with Exo+ sEV increased Tfgf‐β expression in glial cells upon LPS stimulation. An increase in PPAR (Peroxisome proliferator activated receptor) expression was observed upon sEV treatment of glial cells.ConclusionUpregulation of MHC‐II and costimulatory molecules on DCs as well as PPAR upregulation in glial cells upon sEVs treatment indicates that sEVs from RAW 264.7 cells can modulate immune response. These results indicate sEVs modulate innate cells such as microglia and DCs and adaptive immune cells such as CD4+ T cells may contribute to therapeutic effect in attenuating chronic pain.

Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.

Divergent Adaptations in Autonomic Nerve Activity and Neuroimmune Signaling Associated With the Severity of Inflammation in Chronic Colitis.

The autonomic nervous system (ANS) is thought to play a critical role in the anti-inflammatory reflex pathway in acute colitis via its interaction with the spleen and colon. Inflammation in the intestine is associated with a blunting of vagal signaling and increased sympathetic activity. As a corollary, methods to restore sympatho-vagal balance are being investigated as therapeutic strategies for the treatment of intestinal inflammation. Nevertheless, it is indefinite whether these autonomic signaling adaptations in colitis are detrimental or beneficial to controlling intestinal inflammation. In this study, models of moderate and severe chronic colitis are utilized to resolve the correlations between sympatho-vagal signaling and the severity of intestinal inflammation. Spleens and colons were collected from Winnie (moderate colitis), Winnie-Prolapse (severe colitis), and control C57BL/6 mice. Changes to the size and histomorphology of spleens were evaluated. Flow cytometry was used to determine the expression of adrenergic and cholinergic signaling proteins in splenic B and T lymphocytes. The inflammatory profile of the spleen and colon was determined using a RT-PCR gene array. Blood pressure, heart rate, splanchnic sympathetic nerve and vagus nerve activity were recorded. Spleens and colons from Winnie and Winnie-Prolapse mice exhibited gross abnormalities by histopathology. Genes associated with a pro-inflammatory response were upregulated in the colons from Winnie and further augmented in colons from Winnie-Prolapse mice. Conversely, many pro-inflammatory markers were downregulated in the spleens from Winnie-Prolapse mice. Heightened activity of the splanchnic nerve was observed in Winnie but not Winnie-Prolapse mice. Conversely, vagal nerve activity was greater in Winnie-Prolapse mice compared with Winnie mice. Splenic lymphocytes expressing α1 and β2 adrenoreceptors were reduced, but those expressing α7 nAChR and producing acetylcholine were increased in Winnie and Winnie-Prolapse mice. Sympathetic activity may correlate with an adaptive mechanism to reduce the severity of chronic colitis. The Winnie and Winnie-Prolapse mouse models of moderate and severe chronic colitis are well suited to examine the pathophysiology of progressive chronic intestinal inflammation.

Bisphenol A (BPA) Leading to Obesity and Cardiovascular Complications: A Compilation of Current In Vivo Study.

BPA is one of the most common endocrine disruptors that is widely being manufactured daily nationwide. Although scientific evidence supports claims of negative effects of BPA on humans, there is also evidence suggesting that a low level of BPA is safe. However, numerous in vivo trials contraindicate with this claim and there is a high possibility of BPA exposure could lead to obesity. It has been speculated that this does not stop with the exposed subjects only, but may also cause transgenerational effects. Direct disruption of endocrine regulation, neuroimmune and signaling pathways, as well as gut microbiata, has been identified to be interrupted by BPA exposure, leading to overweight or obesity. In these instances, cardiovascular complications are one of the primary notable clinical signs. In regard to this claim, this review paper discusses the role of BPA on obesity in the perspective of endocrine disruptions and possible cardiovascular complications that may arise due to BPA. Thus, the aim of this review is to outline the changes in gut microbiota and neuroimmune or signaling mechanisms involved in obesity in relation to BPA. To identify potentially relevant articles, a depth search was done on the databases Nature, PubMed, Wiley Online Library, and Medline & Ovid from the past 5 years. According to Boolean operator guideline, selected keywords such as (1) BPA OR environmental chemical AND fat OR LDL OR obese AND transgenerational effects or phenocopy (2) Endocrine disruptors OR chemical AND lipodystrophy AND phenocopy (3) Lipid profile OR weight changes AND cardiovascular effect (4) BPA AND neuroimmune OR gene signaling, were used as search terms. Upon screening, 11 articles were finalized to be further reviewed and data extraction tables containing information on (1) the type of animal model (2) duration and dosage of BPA exposure (3) changes in the lipid profile or weight (4) genes, signaling mechanism, or any neuroimmune signal involved, and (5) transgenerational effects were created. In toto, the study indicates there are high chances of BPA exposure affecting lipid profile and gene associated with lipolysis, leading to obesity. Therefore, this scoping review recapitulates the possible effects of BPA that may lead to obesity with the evidence of current in vivo trials. The biomarkers, safety concerns, recommended dosage, and the impact of COVID-19 on BPA are also briefly described.

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development.

Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol’s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol’s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood.

Somatosensory and autonomic neuronal regulation of the immune response

Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases.

Is the Neuroimmune System a Therapeutic Target for Opioid Use Disorder? A Systematic Review.

Opioid use disorder (OUD) is an epidemic in the United States. In the past 12 months alone, there have been 75,000+ deaths attributed to opioid overdose: more than any other year in American history. Current pharmacotherapies for the treatment of OUD effectively suppress opioid withdrawal symptoms, but long-term relapse rates remain unacceptably high. Novel treatments for OUD are desperately needed to curb this epidemic. One target that has received considerable recent interest is the neuroimmune system. The neuroimmune system is anchored by glial cells, i.e., microglia and astrocytes, but neuroimmune signaling is known to influence neurons, including altering neurotransmission, synapse formation, and ultimately, brain function. Preclinical studies have shown that experimental attenuation of pro-inflammatory neuroimmune signaling modulates opioid addiction processes, including opioid reward, tolerance, and withdrawal symptoms, which suggests potential therapeutic benefit in patients. Whereas the peripheral immune system in OUD patients has been studied for decades and is well-understood, little is known about the neuroimmune system in OUD patients or its viability as a treatment target. Herein, we review the literature describing relationships between opioid administration and the neuroimmune system, the influence of neuroimmune signaling on opioid addiction processes, and the therapeutic potential for targeting the neuroimmune system in OUD subjects using glial modulator medications.

Cholinergic REST-G9a gene repression through HMGB1-TLR4 neuroimmune signaling regulates basal forebrain cholinergic neuron phenotype

Cholinergic REST-G9a gene repression through HMGB1-TLR4 neuroimmune signaling regulates basal forebrain cholinergic neuron phenotype

Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice.

The prevalence of Alzheimer’s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1β, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1β, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPβ at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aβ pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.

Inflammatory cytokines and alcohol use disorder: systematic review and meta-analysis.

Objective:To assess differences in blood inflammatory cytokines between people with alcohol use disorder (AUD) and healthy controls (HC).Methods:Searches were performed from inception through April 14, 2021. Meta-analyses with random-effects models were used to calculate the standardized mean difference ([SMD], 95%CI), and potential sources of heterogeneity were explored trough meta-regressions and subgroup analysis.Results:The meta-analysis included 23 studies on the following 14 cytokines: tumor necrosis factor (TNF)-α, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL15, interferon (IFN)-γ and sCD14. There were significantly higher concentrations of IL-6 (n=462 AUD and 408 HC; SMD = 0.523; 95%CI 0.136-0.909; p = 0.008) in AUD than HC. No significant differences were found in the other 13 cytokines.Conclusion:We found that IL-6 levels were significantly higher in individuals with AUD than HC and that other cytokines were not altered. This can be explained by the small number of studies, their methodological heterogeneity, and confounding factors (active use, abstinence, quantity, and physical or psychiatric illnesses, for example). Despite a great deal of evidence about alcohol and inflammatory diseases, studies assessing the role of neuroimmune signaling in the development and severity of AUD are still lacking.

Mas-Related G Protein-Coupled Receptors (Mrgprs) as Mediators of Gut Neuro-Immune Signaling.

Over the past 15years, the research field on Mas-related G protein-coupled receptors (Mrgprs), a relatively new family of rhodopsin A-like G protein-coupled receptors, has expanded enormously, and a plethora of recent studies have provided evidence that several of these Mrgpr family members play an important role in the underlying mechanisms of itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses. Initial studies mainly focused on the skin, but more recently also visceral organs such as the respiratory and gastrointestinal (GI) tracts emerged as sites for Mrgpr involvement. It has become clear that the gastrointestinal tract and its innervation in close association with the immune system represent a novel expression site for Mrgprs where they contribute to the interoceptive mechanisms maintaining homeostasis and might constitute promising targets in chronic abdominal pain disorders. In this short review, we provide an update of our current knowledge on the expression, distribution, and function of members of this Mrgpr family in intrinsic and extrinsic neuro-immune pathways related to the gastrointestinal tract, their mediatory role(s) in gut neuro-immune signaling, and their involvement in visceral afferent (nociceptive) pathways.

Tmem160 contributes to the establishment of discrete nerve injury-induced pain behaviors in male mice.

Chronic pain is a prevalent medical problem, and its molecular basis remains poorly understood. Here, we demonstrate the significance of the transmembrane protein (Tmem) 160 for nerve injury-induced neuropathic pain. An extensive behavioral assessment suggests a pain modality- and entity-specific phenotype in male Tmem160 global knockout (KO) mice: delayed establishment of tactile hypersensitivity and alterations in self-grooming after nerve injury. In contrast, Tmem160 seems to be dispensable for other nerve injury-induced pain modalities, such as non-evoked and movement-evoked pain, and for other pain entities. Mechanistically, we show that global KO males exhibit dampened neuroimmune signaling and diminished TRPA1-mediated activity in cultured dorsal root ganglia. Neither these changes nor altered pain-related behaviors are observed in global KO female and male peripheral sensory neuron-specific KO mice. Our findings reveal Tmem160 as a sexually dimorphic factor contributing to the establishment, but not maintenance, of discrete nerve injury-induced pain behaviors in male mice.

Synaptic effects of IL-1β and CRF in the central amygdala after protracted alcohol abstinence in male rhesus macaques.

A major barrier to remission from an alcohol use disorder (AUD) is the continued risk of relapse during abstinence. Assessing the neuroadaptations after chronic alcohol and repeated abstinence is important to identify mechanisms that may contribute to relapse. In this study, we used a rhesus macaque model of long-term alcohol use and repeated abstinence, providing a platform to extend mechanistic findings from rodents to primates. The central amygdala (CeA) displays elevated GABA release following chronic alcohol in rodents and in abstinent male macaques, highlighting this neuroadaptation as a conserved mechanism that may underlie excessive alcohol consumption. Here, we determined circulating interleukin-1β (IL-1β) levels, CeA transcriptomic changes, and the effects of IL-1β and corticotropin releasing factor (CRF) signaling on CeA GABA transmission in male controls and abstinent drinkers. While no significant differences in peripheral IL-1β or the CeA transcriptome were observed, pathway analysis identified several canonical immune-related pathways. We addressed this potential dysregulation of CeA immune signaling in abstient drinkers with an electrophysiological approach. We found that IL-1β decreased CeA GABA release in controls while abstinent drinkers were less sensitive to IL-1β's effects, suggesting adaptations in the neuromodulatory role of IL-1β. In contrast, CRF enhanced CeA GABA release similarly in controls and abstinent drinkers, consistent with rodent studies. Notably, CeA CRF expression was inversely correlated with intoxication, suggesting that CRF levels during abstinence may predict future intoxication. Together, our findings highlight conserved and divergent actions of chronic alcohol on neuroimmune and stress signaling on CeA GABA transmission across rodents and macaques.

Eosinophil extracellular traps drive asthma progression through neuro-immune signals.

Eosinophilic inflammation is a feature of allergic asthma. Despite mounting evidence showing that chromatin filaments released from neutrophils mediate various diseases, the understanding of extracellular DNA from eosinophils is limited. Here we show that eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid are associated with the severity of asthma in patients. Functionally, we find that EETs augment goblet-cell hyperplasia, mucus production, infiltration of inflammatory cells and expressions of type 2 cytokines in experimental non-infection-related asthma using both pharmaceutical and genetic approaches. Multiple clinically relevant allergens trigger EET formation at least partially via thymic stromal lymphopoietin in vivo. Mechanically, EETs activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, which is potentiated by eosinophil peroxidase. Subsequently, the pulmonary neuroendocrine cells amplify allergic immune responses via neuropeptides and neurotransmitters. Therapeutically, inhibition of CCDC25 alleviates allergic inflammation. Together, our findings demonstrate a previously unknown role of EETs in integrating immunological and neurological cues to drive asthma progression.

Neuroimmune signatures in chronic low back pain subtypes.

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

Neuroimmunomodulation in allergic rhinitis

The role of neuroimmunomodulation in allergic diseases is a research hotspot in recent years. Allergic rhinitis（AR） is caused by overactive immune response to a foreign antigen in nasal mucosa. Immune cells release inflammatory mediators（including histamine, cytokines and neurotrophins）, which directly activate peripheral neurons to mediate nasal congestion, itching, sneezing, and other hyperresponsive symptoms. Upon activation, these peripheral neurons release neurotransmitters （including acetylcholine and norepinephrine） and neuropeptides（including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide） that directly act on immune cells to drive allergic inflammation. Neuro-immune signaling may play a significant role in the pathophysiology of AR. Therefore, a better understanding of these cellular and molecular neuro-immune interactions may inspire the discovery of new targets and novel therapies.

Increased Toll-like Receptor-MyD88-NFκB-Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder.

BackgroundMany brain disorders, including alcohol use disorder (AUD), are associated with induction of multiple proinflammatory genes. One aspect of proinflammatory signaling is progressive increases in expression across cells and induction of other innate immune genes. High‐mobility group box 1 (HMGB1) heteromers contribute to amplification by potentiating multiple proinflammatory responses, including Toll‐like receptors (TLRs). TLR signaling recruits coupling proteins linked to nuclear transcription factors that induce proinflammatory cytokines and chemokines and their respective receptors. We tested the hypothesis that AUD induction of TLR expression increases levels of proinflammatory genes and cellular signaling cascades in association with neurodegeneration in the orbitofrontal cortex (OFC).MethodsPostmortem human OFC tissue samples (n = 10) from males diagnosed with AUD were compared to age‐matched moderate drinking controls (CON). Neuroimmune signaling molecules were assessed using immunohistochemistry for protein and reverse transcription polymerase chain reaction for messenger RNA (mRNA).ResultsIn the AUD OFC, we report induction of the endogenous TLR agonist HMGB1 as well as all TLRs assessed (i.e., TLR2‐TLR9) except TLR1. This was accompanied by increased expression of the TLR adaptor protein myeloid differentiation primary response 88 (MyD88), activation of the proinflammatory nuclear transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), and downstream induction of proinflammatory cytokines, chemokines, and their corresponding receptors. Several of these proinflammatory signaling markers are expressed in glia and neurons. The induction of HMGB1‐TLR‐MyD88‐NFκB proinflammatory signaling pathways correlates with neurodegeneration (i.e., Fluoro‐Jade B), lifetime alcohol consumption, and age of drinking onset.ConclusionThese data implicate the induction of HMGB1‐TLR‐MyD88‐NFκB cascades through coordinated glial and neuronal signaling as contributors to the neurodegeneration seen in the postmortem human OFC of individuals with AUD.