Loss of MicroRNA29 expression in B cells and skin microbiota synergize to promote atopic dermatitis in mice 2581

Abstract Description Our research focuses on the role of the microRNA(miR)29 family to regulate peripheral B cell survival and function. We hypothesized that mice with miR29-deficient B cells (B29KO) would have reduced B cell survival and heightened autoreactive B cell receptors (BCRs). Our investigations using B29KO mice revealed a novel target transcript, Il4ra. B29KO mice develop itching and skin inflammation, with a 50% mortality rate. We found B29KO B cells have higher expression of Il4ra by both qPCR and single-cell sequencing. Differential gene analysis and pathway enrichment show, relative to littermate controls, miR29-deficient B cells exhibit heightened IL4 signaling, reduced activation, and negative regulation of cytokine production. When B29KO B cells are stimulated with IL-4 and anti-CD40 ex vivo, they exhibit greater class switching to IgE than wild-type B cells, a finding recapitulated in B29KO mice that have higher serum IgE titers. To rescue the phenotype, B29KO mice were treated with a neutralizing anti-IL4Ra antibody fully rescued the mice from mortality, confirming the importance of IL-4 signaling to this phenotype. We found that skin swabs from phenotypic B29KO mice transferred the phenotype to healthy B29KO mice but not littermate controls. Donor and recipient mice were found to be colonized with Staphylococcus aureus and xylosus. This work supports a role for miR29 in regulating susceptibility to atopic dermatitis in mice via genetic susceptibility and microbial triggers. Funding Sources NIAID 3R43AI136141, BSF, Bernard Levine Fellowship Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)