Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

Abstract

In pulmonary fibrosis, the transcription factor JUN is highly expressed in the fibrotic foci. Its induction in adult mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and the secretome of individual fibroblasts and leukocytes from pulmonary fibrosis patients. We show that JUN is activated in fibroblasts derived from fibrotic lungs which also demonstrated increased CD47 and PD-L1 expression. Using ATAC-seq and ChIP-seq, we found that activation of JUN in fibroblasts rendered enhancers of CD47 and PD-L1 accessible, an observation that reporter assays corroborated.Meanwhile we detected increased IL-6 signaling which amplified both JUN-mediated CD47-enhancer activity and protein expression in fibrotic lung fibroblasts. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47, and PD-L1 reversed fibrosisincreased phagocytosis of profibrotic fibroblasts and elimination of suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote the fibrotic process and suggest a complementary therapeutic approach that could be used alongside conventional antifibrotics for pulmonary fibrosis diseases.

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models

“…S6D). In bleomycin-induced lung fibrosis, IL-6 is both proinflammatory and profibrotic ( 13 , 23 ). Collectively, these findings suggest that in human cells, JUN expression modifies the communication between fibroblasts and immune cells.…”

AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency

“…Additionally, our findings have important implications for therapeutic interventions for fatal diseases caused by fibroblast-mediated scarring, such as idiopathic pulmonary fibrosis. Indeed, c-Jun overexpression has been shown to be sufficient to drive the disease via downstream targets, including inflammatory cytokines, immune checkpoints, and secreted collagens (51,52). c-Jun/AP-1 has also been demonstrated to act in concert with BAF and cell type-specific transcription factors to regulate chromatin accessibility and gene expression in diverse cell types such as T cells, fibroblasts, and neurons (53).…”

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

“…These factors include FOSL2, JUN, FOS::JUN, FOSL1::JUN, and FOS::JUND. FOS and JUN signaling within fibroblasts has been previously noted to promote the development of a pro-fibrotic gene program, 58 has increased expression in human aneurysm, 59 and has been implicated in the development of atherosclerosis. 60…”