Context-dependent miR-21 regulation of TLR7-mediated autoimmune and foreign antigen driven antibody-forming cell and germinal center responses

Abstract

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), though the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. Herein, using the TLR7 agonist imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody forming cells (AFC), without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21 deficient Sle1b (Sle1b.miR-21KO) mice that were associated with reduced interferon, proinflammatory cytokines, and effector CD4+ T cell responses. RNAseq analysis on B cells from Sle1b.miR-21KO mice revealed reduced activation and response to interferon and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I interferon stimulation. Our findings in the B6.Sle1b.Yaa spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and Tfh responses. Finally, immunization with T-dependent antigen revealed a role for miR-21 in foreign antigen driven GC and Ab, but not AFC responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign antigen driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development. Key PointsO_LImiR-21 has context dependent effects on AFC and GC responses C_LIO_LImiR-21 promotes TLR7-driven autoimmunity with activation of multiple B cell pathways C_LIO_LImiR-21 is required for optimal B cell responses to T-dependent foreign antigen C_LI