Context-dependent mir-21 regulation of tlr7-mediated autoimmune and foreign antigen-driven antibody-forming cell and germinal center responses

Stephanie L. Schell, Kristen N. Bricker, Adam J. Fike, Sathi Babu Chodisetti, Phillip P. Domeier, Nicholas M. Choi, Melinda J. Fasnacht, Sara A. Luckenbill, Steven F. Ziegler, Ziaur S.M. Rahman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), although 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. In this study, 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-producing Ab-forming cells (AFCs) 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 mice that were associated with reduced IFN, proinflammatory cytokines, and effector CD4+ T cell responses. RNA sequencing analysis on B cells from miR-21-deficient Sle1b mice revealed reduced activation and response to IFN, and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I IFN stimulation. Our findings in the B6.Sle1b.Yaa (Sle1bYaa) spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and T follicular helper responses. Finally, immunization with T-dependent Ag revealed a role for miR-21 in foreign Ag-driven GC and Ab, but not AFC, responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign Ag-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.

Original languageEnglish (US)
Pages (from-to)2803-2818
Number of pages16
JournalJournal of Immunology
Volume206
Issue number12
DOIs
StatePublished - Jun 15 2021

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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