Loss of microRNA-29 in B cells leads to atopic skin phenotype in mice

Abstract Developing B cells are highly dependent on microRNA (miRNA) regulation. We have previously demonstrated the miR-29 family of miRNAs contributes to the regulation of B cell survival through fine-tuning of PTEN expression, a negative regulator of B cell receptor (BCR) signaling. When the miR-29 alleles are selectively deleted in B cells, this leads to reduced survival which can be rescued by ablating one copy of Ptento restore normal BCR signaling. We observed that mice with B cells lacking miR-29 also develop an inflammatory skin phenotype associated with lesions, leukocyte infiltration into the skin, and persistent pruritis. Nearly 50% of miR-29-deficient animals die within 6 months of birth, and ablation of Ptento restore BCR signaling did not improve the survival rate. This suggests that additional targets of miR-29 in B lymphocytes are involved in promoting this inflammatory skin condition. Epidermal thickening, granulocyte plasma cell infiltration in the skin, and high serum IgE titers suggest that miR-29 may contribute to the regulation of IgE-driven immune responses and that in the absence of this miRNA family, animals develop atopic dermatitis. Our bioinformatic analysis revealed that miR29 is predicted to regulate the expression of the Il4Ratranscript, and in vitrodifferentiation assays revealed that miR-29-deficient B cells have a higher propensity for IgE class switch recombination in response to IL-4 and/or IL-13 stimulation compared to wild-type control B cells. We conclude that miR-29 is critical in the regulation of both Ptenand Il4raexpression in mature B cells thereby influencing the survival and function of peripheral B lymphocytes, which can have profound repercussions for the development of autoimmune disease. The Bernard Levine Fellowship