miR-21 promotes B cell autoreactivity, inflammatory signaling, and metabolism in TLR7driven systemic autoimmunity
Journal of Immunology(2023)
Abstract
Abstract MicroRNA-21 (miR-21) is upregulated in SLE patients and promotes disease in 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 in miR-21 (Sle1b YaamiR-21 −/−) resisted autoimmunity development through reduced germinal center (GC) B cell, T follicular helper cell, and plasma cell responses. Sle1b YaamiR-21 −/−mice had reduced serum autoantibody titers and numbers of autoantibody-producing antibody forming cells (AFCs) in the spleen and bone marrow. Downstream of TLR7 signaling, PELI1, a negative regulator of the NF-κB family member c-Rel and a direct target of miR-21, was increased in Sle1b YaamiR-21 −/−B cells. Consequently, Sle1b YaamiR-21 −/−B cells had reduced c-Rel expression and proinflammatory cytokines IL-6 and IL-1β. Additionally, Sle1b YaamiR-21 −/−B cells had reduced oxidative phosphorylation, glycolysis, and mitochondrial membrane potential compared to Sle1b YaaB cells. To define the cell-intrinsic mechanisms, we generated B cell-, T cell- and DC-specific miR-21 conditional knockout (cKO) mice on the Sle1b Yaabackground. Reduced B cell autoreactivity, inflammatory signaling, and metabolism in Sle1b YaamiR-21 −/−mice were recapitulated in B cell-specific miR-21 cKO mice. T cell-specific miR-21 cKO mice had a moderate reduction in cellular responses due to reduced co-stimulatory molecules and glycolysis; however, autoimmune responses remained intact. miR-21 deficiency in DCs had no deficit in cellular or autoimmune responses. Our data substantiate a B cell-intrinsic role for miR-21 in promoting inflammatory signaling and metabolic activity in B cells, leading to autoimmunity.
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Key words
autoimmunity,inflammatory signaling
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