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The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity. Tissue-innervating neurons communicate with local immune and non-immune cells to balance homeostasis and inflammation. Deng, Gillis, Kaplan, and Chiu review some of the most well-defined and compelling pathways by which peripheral neurons regulate autoinflammation, host defense, and tissue repair. They discuss recent studies in murine models and invertebrates, demonstrating that neurons have served as immune effectors and/or regulators throughout evolution. [ABSTRACT FROM AUTHOR]

Communication between the nervous system and immune system is important for regulating immunity in health and disease. Yu et al. (2022) show that neuropeptide Y and its homolog NPF serve as a "language" to facilitate crosstalk between these two systems across species, enabling neurons to downregulate harmful immune responses. [ABSTRACT FROM AUTHOR]

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus , a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch. [Display omitted] • S. aureus induces itch and scratch damage with epicutaneous skin exposure • V8 protease (SspA) is necessary and sufficient for itch during S. aureus exposure • S. aureus V8 activates mouse and human sensory neurons through PAR1 • PAR1 deficiency or blockade abrogates S. aureus -induced itch and skin damage Itch evokes a desire to scratch, but the link between microbes and itch was unclear. Staphylococcus aureus , a bacterial pathogen, secretes a protease V8 that activates PAR1 expressed on neurons to drive itch and skin damage. [ABSTRACT FROM AUTHOR]

The opportunistic pathogen Staphylococcus aureus frequently colonizes the inflamed skin of people with atopic dermatitis (AD) and worsens disease severity by promoting skin damage. Here, we show, by longitudinally tracking 23 children treated for AD, that S. aureus adapts via de novo mutations during colonization. Each patient's S. aureus population is dominated by a single lineage, with infrequent invasion by distant lineages. Mutations emerge within each lineage at rates similar to those of S. aureus in other contexts. Some variants spread across the body within months, with signatures of adaptive evolution. Most strikingly, mutations in capsule synthesis gene capD underwent parallel evolution in one patient and across-body sweeps in two patients. We confirm that capD negativity is more common in AD than in other contexts, via reanalysis of S. aureus genomes from 276 people. Together, these findings highlight the importance of the mutation level when dissecting the role of microbes in complex disease. [Display omitted] • Most patients are colonized stably by a single S. aureus sequence type • Within each lineage, de novo variants spread and replace their on-person ancestors • On-person and across-person parallel evolution is observed in capD • Capsule loss enriched on AD patients compared with healthy carriage or other diseases Key et al. investigate the spatial and temporal evolution of S. aureus on children with atopic dermatitis (AD). Patients are stably colonized by a single lineage; however, mutations emerge within each lineage and spread across the body. Mutations in a capsule production gene showed signatures of context-dependent adaptation. [ABSTRACT FROM AUTHOR]

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier. [Display omitted] • The choroid plexus (ChP) is a hub of immune activity following acute brain inflammation • Live imaging reveals immune cell recruitment to the ChP from the brain and periphery • Specialized ChP epithelial cells coordinate stepwise responses to inflammation • Macrophages participate in ChP barrier repair The choroid plexus (ChP) is a hub of immune activity in which a specialized population of epithelial cells coordinates stepwise immune cell recruitment, infiltration, differentiation, and adhesion to the ChP upon acute brain inflammation. Such coordination contributes to the timely breakdown and repair of the ChP brain barrier. [ABSTRACT FROM AUTHOR]

Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process. [Display omitted] • Microbiota-induced T cells accelerate sensory neuron regeneration upon injury • Injury promotes the expression of IL-17RA in dorsal root ganglion sensory neurons • IL-17/IL-17RA axis promotes peripheral sensory neuron regeneration Tissue-resident commensal-specific T cells accelerate peripheral sensory neuron regeneration upon injury via IL-17A. [ABSTRACT FROM AUTHOR]

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection. [Display omitted] • Nav1.8+CGRP+ nociceptors neighbor goblet cells and induce rapid mucus secretion • Commensals trigger CGRP release, which signals to Ramp1 expressed by goblet cells • Nociceptor or Ramp1 ablation leads to decreased mucus levels and microbial dysbiosis • Neuron-goblet cell signaling via a CGRP-Ramp1 axis protects against colitis Pain sensory neurons induce mucus release from nearby intestinal goblet cells via a CGRP-Ramp1 axis in response to commensal and dietary cues to orchestrate gut mucosal protection. [ABSTRACT FROM AUTHOR]

Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the biosynthetic gene N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr(-/-) mice. When placed on an atherogenic diet, Ldlr(-/-)Ndst1(f/f)LysMCre(+) mice had increased atherosclerotic plaque area and volume compared to Ldlr(-/-) mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression; increased macrophages in plaques; increased expression of ACAT2, a key enzyme in cholesterol ester storage; and increased foam cell conversion. Motif analysis of promoters of upregulated genes suggested increased type I interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-β. The proinflammatory macrophages derived from Ndst1(f/f)LysMCre(+) mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining type I interferon reception in a quiescent state through sequestration of IFN-β., (Copyright © 2014 Elsevier Inc. All rights reserved.)