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MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE218834 | GEO | 2024/09/10

REPOSITORIES: GEO

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"MrgprA3 neurons selectively control myeloid-derived cytokines for IL-17 dependent cutaneous immunity".

Project description:Skin employs interdependent cellular networks to facilitate barrier integrity and host immunity through ill-defined mechanisms. This study demonstrates that manipulation of itch-sensing neurons bearing the Mas-related G protein-coupled receptor A3 (MrgprA3) drives IL-17+ γδ T cell expansion, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni through mechanisms that require myeloid antigen presenting cells (APC). Activated MrgprA3 neurons instruct myeloid APCs to downregulate interleukin 33 (IL-33) and up-regulate TNFα partially through the neuropeptide calcitonin gene related peptide (CGRP). Strikingly, cell-intrinsic deletion of IL-33 in myeloid APC basally alters chromatin accessibility at inflammatory cytokine loci and promotes IL-17/23-dependent epidermal thickening, keratinocyte hyperplasia, and resistance to helminth infection. Our findings reveal a previously undescribed mechanism of intercellular cross-talk wherein "itch" neuron activation reshapes myeloid cytokine expression patterns to alter skin composition for cutaneous immunity against invasive pathogens.

| S-EPMC10705600 | biostudies-literature

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [scRNA-Seq]

Project description:Skin contains poorly understood interdependent cellular networks that facilitate barrier integrity and host immunity, including neurons, and myeloid cells; the latter of which intrinsically express the pleiotropic cytokine IL-33. This work shows selective suppression of IL-33 expression in myeloid cells by activation of itch-sensing neurons bearing the Mas-related G protein receptor A3 (A3). Optogenetic activation of A3 neurons also increased IL-17-expressing γδ T cells, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni, partially through the neuropeptide CGRP. Cell-intrinsic loss of IL-33 in myeloid cells alters chromatin conformation, basally elevates expression and release of IL-17-inducing cytokines (e.g., IL-1β, IL-6), and expands macrophage and cDC2 differentiation, driving both tissue pathology (e.g., epidermal thickening, keratinocyte hyperplasia) and resistance to helminth infection. Our findings suggest a mechanism of cellular cross-talk allowing “itch” neuron activation to alter myeloid composition and cytokine expression patterns for reshaping skin architecture and driving immunity

2024-09-12 | GSE218825 | GEO

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [ATAC-Seq]

2024-09-12 | GSE218833 | GEO

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [bulk RNA-Seq]

2024-09-12 | GSE218826 | GEO

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity

Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity

| PRJNA905825 | ENA

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [scRNA-Seq]

Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [scRNA-Seq]

| PRJNA905813 | ENA

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [ATAC-Seq]

Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [ATAC-Seq]

| PRJNA905826 | ENA

MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [bulk RNA-Seq]

Project description:MrgprA3 neurons selectively control myeloid-derived IL-33 for IL-17 dependent cutaneous immunity [bulk RNA-Seq]

| PRJNA905814 | ENA

Cutaneous TRPV1<sup>+</sup> Neurons Trigger Protective Innate Type 17 Anticipatory Immunity.

Project description:Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.

| S-EPMC6788801 | biostudies-literature

Molecular Signature of Pruriceptive MrgprA3<sup>+</sup> Neurons.

Project description:Itch, initiated by the activation of sensory neurons, is associated frequently with dermatological diseases. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulation of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here, we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are a direct neuronal target for histamine and Mrgpr agonists. In addition, PTPN6 and PCDH12 were identified as highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potential targets for combating itch.

| S-EPMC7529694 | biostudies-literature

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