Unifying mechanism for different fibrotic diseases

Abstract

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun–mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

“…TGF-β activation and altered c-JUN signaling were also recently confirmed in PMF patients and in animal models by the Weissman Laboratory [114]. Since activation of c-JUN may represent one of the signaling which may result in activation of macrophages, which are present in higher frequency in the blood of Gata1 low mice ( Table 2 ), into myelofibrotic-specific niches [115].…”

“…Since activation of c-JUN may represent one of the signaling which may result in activation of macrophages, which are present in higher frequency in the blood of Gata1 low mice ( Table 2 ), into myelofibrotic-specific niches [115]. drugs targeting c-JUN and macrophages have been proposed as therapeutic strategies for PMF because they may be more specific and have less toxic effects than TGF-β inhibitor [114]. …”

Black, White, and Gray: Macrophages in Skin Repair and Disease

“…Fibrolytic macrophages remain to be characterized, however, a recent study has shown that macrophages can be therapeutically activated to take up and degrade excessive cellular components present in the fibrotic microenvironment. This study shows that similar to cancer cells, fibrosis is marked by increased CD47 on fibroblasts or the “don’t eat me signal” through activation of the c-Jun pathway 78 . Presence of this protective signal allows fibrotic cells to evade the immune response.…”

“…Presence of this protective signal allows fibrotic cells to evade the immune response. Inhibition of CD47 can resolve fibrosis through blocking the “don’t eat me signal” and allowing phagocytosis by macrophages 78 .…”

Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease

“…Notably, the five hub genes of the tubulointerstitial PIN all encode transcription factors, four of which are subunits of AP-1 transcription factors (JUN, FOS, ATF3, and JUND) with a complex role in regulating cell life and death [37]. Interestingly, a recent study demonstrated that many fibrotic diseases share the activation of JUN (also known as c-Jun) in fibroblasts, leading to enhanced cell proliferation and migration [38]. Considering that tubular injury leads to epithelial cell cycle arrest [39], it is not surprising that the level of JUN mRNA was significantly downregulated in diseased tubules.…”