Neuroimmune Axis Research Articles

Targeting the cholinergic anti-inflammatory pathway: an innovative strategy for treating diseases.

The cholinergic anti-inflammatory pathway (CAP) is comprised of the vagus nerve, acetylcholine, nicotinic acetylcholine receptors, the spleen, and the splenic nerve. It represents a sophisticated neuroimmune axis that critically regulates the crosstalk between the nervous system and the immune response via the vagus nerve. Here, we provided a nuanced exploration of the CAP's role in curbing inflammatory processes and its broad therapeutic potential across a spectrum of diseases. We meticulously dissect the intricate mechanisms by which the CAP modulates key signaling cascades, including the NF-κB, JAK2/STAT3, MAPK/ERK, PI3K/AKT, COX2/PGE2, and NRF2/HO-1 pathways, which are quintessential in the pathogenesis of various conditions. Additionally, we also summarized the CAP's profound implications in the management of inflammatory diseases, neurodegenerative disorders, metabolic syndromes, and oncological malignancies, elucidating its capacity to mitigate disease severity and progression through sophisticated immune modulation. The modulation of the CAP is suggested as a novel strategy that could potentially transform treatment approaches for a variety of conditions. However, the precise cellular and molecular underpinnings of the CAP's effects, as well as its translatability to clinical settings, remain subjects of ongoing investigation. The review calls for further research to demystify the mechanisms of the CAP and to harness its therapeutic potential fully, with the aim of developing innovative and efficacious treatment modalities that exploit the pathway's unique attributes.

From pain to meningitis: bacteria hijack nociceptors to promote meningitis.

Bacterial meningitis is a severe and life-threatening infection of the central nervous system (CNS), primarily caused by Streptococcus pneumoniae and Neisseria meningitidis. This condition carries a high risk of mortality and severe neurological sequelae, such as cognitive impairment and epilepsy. Pain, a central feature of meningitis, results from the activation of nociceptor sensory neurons by inflammatory mediators or bacterial toxins. These nociceptors, abundantly present in the meninges, trigger neuroimmune signaling pathways that influence the host immune response. However, the mechanisms by which bacteria hijack these nociceptors to promote CNS invasion and exacerbate the disease remain poorly understood. This review examines the interactions between bacteria and meningeal nociceptors, focusing on their direct and indirect activation via ion channels, such as transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), or through the release of neuropeptides like calcitonin gene-related peptide (CGRP). These interactions suppress immune defenses by inhibiting macrophage activity and neutrophil recruitment, thus facilitating bacterial survival and invasion of the CNS. Understanding this neuroimmune axis may open potential therapeutic targets for treating bacterial meningitis by enhancing host defenses and mitigating pain. Further research using advanced methodologies is essential to clarify the role of nociceptor-mediated immune modulation in this disease.

Nerves at Play: The Peripheral Nervous System in Extracranial Malignancies.

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. Significance: The continued and growing interest in cancer neuroscience by the scientific and medical communities reflects the rapidly accumulating interdisciplinary understanding of the nervous system's modulation of immune, vascular, and cancer cells' functions in malignancies. Understanding these regulatory functions can identify targets for intervention that may already be clinically available for other indications. This potential brings great excitement and hope for patients with cancer worldwide.

Recent advances in the role of neuroregulation in skin wound healing.

Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.

Visual cues of respiratory contagion: Their impact on neuroimmune activation and mucosal immune responses in humans.

This study investigated the neural correlates of perceiving visual contagion cues characteristic of respiratory infections through functional magnetic resonance imaging (fMRI). Sixty-two participants (32f/ 30 m; ∼25 years on average) watched short videos depicting either contagious or non-contagious everyday situations, while their brain activation was continuously measured. We further measured the release of secretory immunoglobulin A (sIgA) in saliva to examine the first-line defensive response of the mucosal immune system. Perceiving sneezing and sick individuals compared to non-contagious individuals triggered increased activation in the anterior insula and other regions of the neuroimmune axis, that have been implicated in the somatosensory representation of the respiratory tract, and further led to increased release of sIgA. In line with predictions, this contagion cue-related activation of the insula was positively correlated with both perceived contagiousness and disgust evoked by the videos, as well as with the mucosal sIgA response. In contrast, the amygdala exhibited heightened activation to all videos featuring humans, regardless of explicit signs of contagion, indicating a nonspecific alertness to human presence. Nevertheless, amygdala activation was also correlated with the disgust ratings of each video. Collectively, these findings outline a neuroimmune mechanism for the processing of respiratory contagion cues. While the insula coordinates central and peripheral immune activation to match the perceived contagion threat, supposedly by triggering both increased sIgA release and contagion-related cognitions, the amygdala may rather act as an alerting system for social situations with a heightened transmission risk. This proactive neuroimmune response may help humans to manage contagion risks, that are difficult to avoid, by activating physiological and cognitive countermeasures in reaction to typical symptoms of respiratory infection, which prepares the organism for subsequent pathogen exposure.

Neuroimmune axis: Linking environmental factors to pancreatic β-cell dysfunction in Diabetes.

Pancreatic β-cells are specialized in secreting insulin in response to circulating nutrients, mainly glucose. Diabetes is one of the most prevalent endocrine-metabolic diseases characterized by an imbalance in glucose homeostasis, which result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and peripheral insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Pancreatic β-cell dysfunction and islet inflammation are common characteristics of both types of the disease. Pancreatic islets are a highly innervated tissue whose function can be influenced by the brain, either directly through the autonomic nervous system or indirectly via neuroendocrine mechanisms. In addition, it is well-established that there is a fine-tuned communication between the immune and neuroendocrine tissues in maintaining endocrine pancreas homeostasis. Various psycho-social, physico-chemical and lifestyle environmental factors have been associated with diabetes risk. In this review, I briefly comment on certain aspects of the psycho-neuro-immune interactions that link environmental factors and the endocrine pancreas, leading to metabolic health or diabetes. Interdisciplinary research, embracing new and broader perspectives, should be conducted to explore strategies for preventing or slowing down the constant increase in diabetes worldwide.

Irisin Attenuates Neuroinflammation Targeting the NLRP3 Inflammasome.

Neuroinflammation is defined as an immune response involving various cell types, particularly microglia, which monitor the neuroimmune axis. Microglia activate in two distinct ways: M1, which is pro-inflammatory and capable of inducing phagocytosis and releasing pro-inflammatory factors, and M2, which has anti-inflammatory properties. Inflammasomes are large protein complexes that form in response to internal danger signals, activating caspase-1 and leading to the release of pro-inflammatory cytokines such as interleukin 1β. Irisin, a peptide primarily released by muscles during exercise, was examined for its effects on BV2 microglial cells in vitro. Even at low concentrations, irisin was observed to influence the NLRP3 inflammasome, showing potential as a neuroprotective and anti-inflammatory agent after stimulation with lipopolysaccharides (LPSs). Irisin helped maintain microglia in their typical physiological state and reduced their migratory capacity. Irisin also increased Arg-1 protein expression, a marker of M2 polarization, while downregulating NLRP3, Pycard, caspase-1, IL-1β, and CD14. The results of this study indicate that irisin may serve as a crucial mediator of neuroprotection, thus representing an innovative tool for the prevention of neurodegenerative diseases.

Macrophage NLRP3 inflammasome mediates the effects of sympathetic nerve on cardiac remodeling in obese rats

Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68+NLRP3+ macrophage infiltration in the hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of the nuclear factor-kappa B (NF-κB) pathway.This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.

Unexpected macrophage-mediated myocardial cGas-STING activation in a novel mouse model of stress-related sleep disturbance

Abstract Background Delayed bedtime following stress disorder is prevalent in waves of pandemics and modern life. Considered to be a specific and important contributor to cardiovascular health, stress-related sleep disturbance has an unmet need in steady preclinical models. We previously found exciting corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) area of mice could induce 3-hour-long wakefulness. Purpose This study aimed to induce reproducible phenotypes of stress-related sleep disturbance in mice and explore the potential impact on cardiac function. Methods The chemogenetic method of designer receptors exclusively activated by designer drugs (DREADD) system was adopted to mimic stress-related sleep disturbance. We transfected PVH CRH neurons with rAAV-hSyn-DIO-hM3Dq-mCherry and rAAV-Crh-CRE. Prolonged CRH neuron activation was induced by daily intraperitoneal injection of clozapine N-oxide (CNO, 3mg/kg) at 9 am. Bulk RNA-sequencing and bioinformatics analysis were conducted for mechanistic exploration. Results 2-week repeated chemogenetic activation of PVH CRH neurons induced a 5-fold corticosterone release, consistent with increased daily 3-hour wakefulness and corresponding decreases in both rapid eye movement (REM) as well as non-REM sleep. Over 30% of chronic CRH activation mice displayed difficulties in maintaining balance and experienced premature mortality. Mice subjected to prolonged CRH activation showed impaired left ventricular ejection fraction (67.9% versus 48.2%, p=0.0011), and a dilated appearance demonstrated by histological staining. Intriguingly, the number of circulating monocytes increased. Then, we performed bulk RNA-sequencing of heart and bone marrow from CRH-activated and control mice. Differential gene expression and gene set enrichment analysis (GSEA) indicated marked activation of interferon-beta-related pathways in both tissues. Cytosolic DNA-sensing pathway and related key effector genes (cGAS, Cxcl10, CCL5) were found up-regulated in the heart, while mitochondrial oxidative phosphorylation was suppressed. We adopted the CIBERSORT tool to estimate immune infiltration in heart tissues and characterized M1 macrophage as the main pro-inflammatory cell. Further, we screened a set of secreted factors and mediators, which might play active roles in inflamed hearts. Conclusion Taken together, we report a failing heart in a mouse model of stress-related sleep disturbance. The neuro-immune axis involvement and molecular mechanisms merit in-depth explorations.

Electrically-driven drug delivery into deep cutaneous tissue by conductive microneedles for fungal infection eradication and protective immunity

Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using in vitro and ex vivo models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue.

Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice

BackgroundIL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation.Main bodySystemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1β, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfβ expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration.ConclusionOverall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.

Brain resident microglia in Alzheimer's disease: foe or friends.

The neurobiology of Alzheimer's disease (AD) is unclear due to its multifactorial nature. Although a wide range of studies revealed several pathomechanisms of AD, dementia is yet unmanageable with current pharmacotherapies. The recent growing literature illustrates the role of microglia-mediated neuroinflammation in the pathogenesis of AD. Indeed, microglia serve as predominant sentinels of the brain, which diligently monitor the neuroimmune axis by phagocytosis and releasing soluble factors. In the case of AD, microglial cells are involved in synaptic pruning and remodeling by producing inflammatory mediators. The conditional inter-transformation of classical activation (proinflammatory) or alternative activation (anti-inflammatory) microglia is responsible for most brain disorders. In this review, we discussed the role of microglia in neuroinflammatory processes in AD following the accumulation of amyloid-β and tau proteins. We also described the prominent phenotypes of microglia, such as disease-associated microglia (DAM), dark microglia, interferon-responsive microglia (IRMs), human AD microglia (HAMs), and microglial neurodegenerative phenotype (MGnD), which are closely associated with AD incidence. Considering the key role of microglia in AD progression, microglial-based therapeutics may hold promise in mitigating cognitive deficits by addressing the neuroinflammatory responses.

Non-invasive ventral cervical magnetoneurography as a proxy of in vivo lipopolysaccharide-induced inflammation

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual’s distinct endophenotype.

Brain-immune interactions: implication for cognitive impairments in Alzheimer's disease and autoimmune disorders.

Progressive memory loss and cognitive dysfunction, encompassing deficits in learning, memory, problem solving, spatial reasoning, and verbal expression, are characteristics of Alzheimer's disease and related dementia. A wealth of studies has described multiple roles of the immune system in the development or exacerbation of dementia. Individuals with autoimmune disorders can also develop cognitive dysfunction, a phenomenon termed "autoimmune dementia." Together, these findings underscore the pivotal role of the neuroimmune axis in both Alzheimer's disease and related dementia and autoimmune dementia. The dynamic interplay between adaptive and innate immunity, both in and outside the brain, significantly affects the etiology and progression of these conditions. Multidisciplinary research shows that cognitive dysfunction arises from a bidirectional relationship between the nervous and immune systems, though the specific mechanisms that drive cognitive impairments are not fully understood. Intriguingly, this reciprocal regulation occurs at multiple levels, where neuronal signals can modulate immune responses, and immune system-related processes can influence neuronal viability and function. In this review, we consider the implications of autoimmune responses in various autoimmune disorders and Alzheimer's disease and explore their effects on brain function. We also discuss the diverse cellular and molecular crosstalk between the brain and the immune system, as they may shed light on potential triggers of peripheral inflammation, their effect on the integrity of the blood-brain barrier, and brain function. Additionally, we assess challenges and possibilities associated with developing immune-based therapies for the treatment of cognitive decline.

The Neuroimmune Axis and Its Therapeutic Potential for Primary Liver Cancer.

The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).

Dopamine β-hydroxylase shapes intestinal inflammation through modulating T cell activation

BackgroundInflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined. MethodsCD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function. ResultsInhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells. ConclusionModulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.

Specific Salivary Neuropeptides Shift Synchronously during Acute Stress in Fire Recruits.

Once thought of as an immune-privileged site, we now know that the nervous system communicates in a bidirectional manner with the immune system via the neuroimmune axis. Neuropeptides constitute a component of this axis, playing critical roles in the brain and periphery. The function of salivary neuropeptides in the acute stress response is not well understood. The purpose of this study is to investigate salivary neuropeptide levels during acute stress. Salivary samples were collected from fire recruits engaged in a stress training exercise previously shown to induce acute stress, at three separate timepoints during the exercise and levels of oxytocin, neurotensin, Substance P, α-MSH, and β-Endorphin were measured using the Human Neuropeptide 5-Plex Custom Assay Eve Technologies. All neuropeptides increased throughout the acute stress simulation and during the recovery phase. Exploratory factor analysis (EFA) identified one factor contributing to baseline values across five neuropeptides and Pairwise Pearson Correlation Coefficient analysis showed positive correlations >0.9 for almost all neuropeptide combinations at the pre-stress timepoint. Further analysis identified negative and positive correlations between past-life trauma and self-assessed hardiness, respectively. Calculated neuropeptide scores showed an overall positive correlation to self-assessed hardiness. Altogether, our results suggest that salivary neuropeptides increase synchronously during acute stress and higher levels correlate with an increase in self-assessed hardiness. Further study is required to determine if interventions designed to enhance neuropeptide activity can increase stress resilience, especially in high-stress occupations such as firefighting.

A body–brain circuit that regulates body inflammatory responses

The body–brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4–6. Here we show that a peripheral immune insult strongly activates the body–brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body–brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

Immune drivers of physiological and pathological pain.

Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.

The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases.

The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.