Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active ...crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The ...peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases.
Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and ...disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons—olfactory chemosensory neurons and nociceptor sensory neurons—detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the “gut–brain axis” to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases.
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•Bacteria communicate with the nervous system in health and disease.•Clostridial neurotoxins target the SNARE complex to block neurotransmission.•C. elegans and mammalian sensory neurons detect bacterial products for olfaction.•Nociceptor sensory neurons detect bacterial PAMPs and toxins to produce pain.•Gut bacteria release metabolites and neurotransmitters that signal to the brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Microbes and pain Deng, Liwen; Chiu, Isaac M
PLOS pathogens
17, Issue:
4
Journal Article
Peer reviewed
Open access
Upon sensing a damaging stimulus, action potentials are transmitted to nociceptor cell bodies in the dorsal root ganglia (DRG), which receive input from peripheral tissues such as the skin. S. aureus ...α-hemolysin activates a broad group of nociceptor neurons which express the Nav1.8 sodium channel and the heat-sensitive ion channel TRPV1. FPR, formyl peptide receptor; LPS, lipopolysaccharide; PSMα, phenol soluble modulin α3; SL-1, sulfolipid-1; SLS, streptolysin S; TLR, Toll-like receptor; TRP, transient receptor potential; TTCC, T-type calcium channels; UPEC, uropathogenic Escherichia coli. https://doi.org/10.1371/journal.ppat.1009398.g001 Streptococcus pyogenes is a causative agent of infections characterized by intense pain such as pharyngitis (strep throat), cellulitis, and necrotizing fasciitis. Local injection of botulinum neurotoxin a (BoNT/A), which blocks neurotransmission, or systemic treatment of mice with BIBN4096, a CGRP receptor antagonist, enhanced host defenses and S. pyogenes bacterial clearance 6. ...S. pyogenes may hijack a neuro-immune suppression mechanism to facilitate their survival.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Principal component analysis (PCA) is a key tool for understanding population structure and controlling for population stratification in genome-wide association studies (GWAS). With the advent of ...large-scale datasets of genetic variation, there is a need for methods that can compute principal components (PCs) with scalable computational and memory requirements. We present ProPCA, a highly scalable method based on a probabilistic generative model, which computes the top PCs on genetic variation data efficiently. We applied ProPCA to compute the top five PCs on genotype data from the UK Biobank, consisting of 488,363 individuals and 146,671 SNPs, in about thirty minutes. To illustrate the utility of computing PCs in large samples, we leveraged the population structure inferred by ProPCA within White British individuals in the UK Biobank to identify several novel genome-wide signals of recent putative selection including missense mutations in RPGRIP1L and TLR4.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The peripheral nervous and immune systems are traditionally thought of as serving separate functions. The line between them is, however, becoming increasingly blurred by new insights into neurogenic ...inflammation. Nociceptor neurons possess many of the same molecular recognition pathways for danger as immune cells, and, in response to danger, the peripheral nervous system directly communicates with the immune system, forming an integrated protective mechanism. The dense innervation network of sensory and autonomic fibers in peripheral tissues and high speed of neural transduction allows rapid local and systemic neurogenic modulation of immunity. Peripheral neurons also seem to contribute to immune dysfunction in autoimmune and allergic diseases. Therefore, understanding the coordinated interaction of peripheral neurons with immune cells may advance therapeutic approaches to increase host defense and suppress immunopathology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of ...the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund’s adjuvant (CFA) as a model of adjuvant- and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G⁺CD11b⁺ neutrophils and T-cell receptor (TCR) β⁺ T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b⁺Ly6G⁻ myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2⁺Ly6Chi) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b⁺Ly6G⁻ myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal ...cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). We found that SOD1G93A microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer’s disease genes, are concurrently upregulated. Mutant microglia differed from SOD1WT, lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation.
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•Identification of specific marker genes for acutely isolated microglia•Progressive resident microglia transcriptome changes reveal in vivo activation phenotype•Microglial ALS disease activation signature distinct from M1/M2 macrophages•Parallel transcriptome and FACS analyses reveal T cell/microglia crosstalk
Microglia are resident immune cells of the brain that are activated by infection or tissue damage. In this study, Maniatis and colleagues report the acute isolation, transcriptional profiling, and immunological analysis of microglia during disease activation in an ALS mouse model. A neurodegeneration-specific gene-expression signature is identified that includes induction of both neuroprotective and toxic factors and is distinct from that associated with M1/M2 macrophages. The data also provide a resource for future studies of microglia activation in neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)
, but so far there has been little scientific validation of this link. Here we ...report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics
, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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