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MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33

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 drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33

Project description:MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33

| PRJNA905825 | ENA

"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 [ATAC-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 | GSE218833 | GEO

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

2024-09-12 | GSE218825 | 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 [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 [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 [bulk RNA-Seq]

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

| PRJNA905814 | ENA

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms.

Project description:Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4(+) T helper 2 cells (T(H)2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4(+) T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection.

| S-EPMC3538196 | 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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