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Neutrophil-specific defensin receptors prevent skin dysbiosis and bacterial infection

ABSTRACT: Healthy skin maintains a diverse microbiome and a potent immune system to fight off infections. In this study, we discovered that epithelium-derived antimicrobial peptides defensins activate orphan GPCRs Mrgpra2a/b on neutrophils. This signaling axis is required for effective neutrophil-mediated skin immunity and microbiome homeostasis. We generated two mutant mouse lines, Defensin conditional knockout (Def cKO, K14-cre; Def fl/fl) in which the entire Def gene cluster is conditionally deleted from keratinocytes, and Mrgpra2 double knockout (Mrgpra2 dKO). We used high-throughput RNA sequencing to evaluate the whole transcriptomes of WT and mutant animals' skin under naive condition and 24 hours post-S. aureus infection. Disruption of defensin-Mrgpra2 signaling caused reduction of a network of pro-inflammatory and antibacterial gene expression. This study demonstrates the importance of epithelial-neutrophil signaling via the defensin-Mrgpra2 axis in maintaining healthy skin ecology and promoting antibacterial host defense.

ORGANISM(S): Mus musculus

PROVIDER: GSE178507 | GEO | 2021/10/01

REPOSITORIES: GEO

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Project description:Objectives: To understand the crosstalk between the immune system and keratinization in psoriatic skin, using a systems biology approach based on transcriptomics, proteomics and microbiome profiling. Methods: We collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions. To assess the systemic nature of the disease, we performed a high-throughput proteome profiling to study the profiles of proteins circulating in the serum of the same donors. Results: We found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using co-expression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a “core” set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the “core network” of genes. We further identified 39 circulating proteins from the serum that were significantly correlated with the corresponding local skin gene expression, highlighting systemic aberrations due to skin disease. Integration of “core” genes identified from skin with circulating protein profiles revealed PI3 as a key biomarker for psoriasis. Conclusions: We identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition. Multi-omics analysis identified PI3 as a psoriasis-specific biomarker for disease severity and potential target for treatment strategies.

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Neutrophil-specific defensin receptors prevent skin dysbiosis and bacterial infection

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