Monoallelic IRF5 deficiency in B cells prevents murine lupus

• Published in: JCI insight Vol. 6; no. 15
• Main Authors: Pellerin, Alex, Yasuda, Kei, Cohen-Bucay, Abraham, Sandra, Vanessa, Shukla, Prachi, Jr, Barry K Horne, Nündel, Kerstin, Viglianti, Gregory A, Xie, Yao, Klein, Ulf, Tan, Ying, Bonegio, Ramon G, Rifkin, Ian R
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 09.08.2021; American Society for Clinical investigation
• Subjects: Animals; Autoimmunity; B-Lymphocytes - metabolism; Disease Models, Animal; Gain of Function Mutation; Gene Expression Regulation - immunology; Germinal Center; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interleukin-6 - metabolism; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Mice; Signal Transduction - immunology; Tumor Necrosis Factor-alpha - metabolism; Autoimmunity; Autoimmune diseases
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.141395

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell-intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.