miR-21 promotes B cell autoreactivity, inflammatory signaling, and metabolism in TLR7-driven systemic autoimmunity

Abstract MicroRNA-21 (miR-21) is upregulated in SLE patients and promotes disease multiple autoimmune mouse models; however, mechanisms by which miR-21 promote autoimmunity are unknown. Here we show that TLR7 overexpressing SLE-prone B6.Sle1b Yaamice deficient (Sle1b YaamiR-21 −/−) resisted development through reduced germinal center (GC) B cell, T follicular helper plasma cell responses. Sle1b −/−mice had serum autoantibody titers numbers of autoantibody-producing antibody forming cells (AFCs) the spleen bone marrow. Downstream signaling, PELI1, a negative regulator NF-κB family member c-Rel direct target miR-21, was increased −/−B cells. Consequently, expression proinflammatory cytokines IL-6 IL-1β. Additionally, oxidative phosphorylation, glycolysis, mitochondrial membrane potential compared to YaaB To define cell-intrinsic mechanisms, generated cell-, cell- DC-specific conditional knockout (cKO) mice on Yaabackground. Reduced autoreactivity, inflammatory metabolism were recapitulated cell-specific cKO mice. moderate reduction cellular responses due co-stimulatory molecules glycolysis; remained intact. deficiency DCs no deficit or Our data substantiate role for promoting signaling metabolic activity cells, leading autoimmunity.