IL-17-driven transcriptional programs in muscle fibroblasts are not required for pathogenesis in murine anti-histidyl-tRNA synthetase (Jo-1) myositis.

Idiopathic inflammatory myopathy (IIM) is a systemic autoimmune disease targeting muscle and extramuscular organs, but the molecular mechanisms driving IIM pathogenesis remain largely undefined. Muscle fibroblasts are central to orchestrating inflammation in myositis. Here, we investigated muscle fibroblast dynamics using a single-cell RNA sequencing approach in an established murine model of anti-histidyl-tRNA synthetase (HRS, also known as Jo-1)-induced myositis. In fibroblasts, there was a robust activation of an IL-17 gene signature during disease. Among the induced genes was Nfkbiz, which encodes IκBζ, a noncanonical NF-κB transcriptional coactivator known to be key for pathologic IL-17 signaling in a variety of autoimmune settings. In muscle fibroblasts, IκBζ was potently activated by IL-17 in vitro and was essential for IL-17 signaling responsiveness. Surprisingly, however, the IL-17-IκBζ signaling axis was dispensable for the histopathological phenotype in HRS-induced myositis. Thus, despite a prominent IL-17 transcriptional signature, IL-17 and IκBζ are not required for autoantibody production or tissue inflammation in this model system.