The ETS transcription factor SPI1/PU.1 controls fibroblast polarization and tissue fibrosis. Homo sapiens

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix which lead to scaring and organ failure. In sharp contrast, hallmark feature of fibroblasts in arthritis is matrix degradation by release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms driving these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts are enigmatic. We identified PU.1 as orchestrating anchor within the network of pro-fibrotic mediators to establish a pro-fibrotic phenotype. The interplay between transcriptional and posttranscriptional mechanisms which normally control PU.1 expression is perturbed in fibrotic diseases such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis, kidney fibrosis and chronic graft-versus-host disease, resulting in upregulation of PU.1, the induction of fibrosis-associated gene sets and a phenotype switch into matrix-producing pro-fibrotic fibroblasts. In contrast, inactivation of PU.1 disrupts the fibrotic network and enables re-programing of fibrotic fibroblasts into resting fibroblasts and regression of fibrosis in different organs. Targeting of PU.1 may thus represent a novel therapeutic approach for the treatment of a wide range of fibrotic diseases. Overall design: PU.1 chromatin marks were assessed in primary human fibroblasts from patients with systemic sclerosis by ChIP-Seq.