Towards a Unified Approach in Autoimmune Fibrotic Signalling Pathways

Abstract

Autoimmunity is a chronic process resulting in inflammation, tissue damage, and subsequent tissue remodelling and organ fibrosis. In contrast to acute inflammatory reactions, pathogenic fibrosis typically results from the chronic inflammatory reactions characterizing autoimmune diseases. Despite having obvious aetiological and clinical outcome distinctions, most chronic autoimmune fibrotic disorders have in common a persistent and sustained production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements or epithelial to mesenchymal transformation (EMT) that progressively remodels and destroys normal tissue architecture leading to organ failure. Despite its enormous impact on human health, there are currently no approved treatments that directly target the molecular mechanisms of fibrosis. The primary goal of this review is to discuss the most recent identified mechanisms of chronic autoimmune diseases characterized by a fibrotic evolution with the aim to identify possible common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…A flourishing research field is focused on the evaluation of the pathways involved in the fibrotic process observed in the salivary glands (SGs) derived from Sjögren’s Syndrome (SS) patients. Fibrogenesis observed in SGs can be considered the end result of chronic, intense inflammatory reactions induced by a variety of stimuli in this autoimmune disease [ 7 , 8 , 58 , 59 ]. Pioneering studies aimed at correlating SS with a fibrotic evolution of the salivary glands were conducted over 10 years ago, demonstrating a significant association between stimulated salivary flow, the focus score, and fibrosis in a high number of SS biopsy specimens.…”

“…More recently, studies have demonstrated an exuberant upregulation of TGF-β1 in SS SGs, which induces the loss of epithelial features and the acquisition of mesenchymal features in SG epithelial cells via triggering of the EMT program through the TGF-β1/Smad/Snail signaling pathway [ 62 ]. Indeed, TGF-β1 seems to be able to regulate EMT through both main pathways: the canonical Smad-dependent and non-canonical Smad-independent signaling pathways [ 7 , 8 , 62 ].…”

“…These cells acquire much higher migratory capabilities and are able to deposit extracellular matrix (ECM) proteins. The triggering of various cascades of molecular interconnected events leads to an exacerbation of the inflammatory state or to tumor proliferation and metastasis, with serious consequences [ 6 , 7 , 8 ]. Despite the fact that fibrosis appears to be a partly reversible process in various clinical studies [ 9 ], unfortunately, therapeutic options are still very limited.…”

Targeting Interleukin-17 as a Novel Treatment Option for Fibrotic Diseases

“…In recent years, growing evidence has highlighted that aberrant fibrosis is also a major pathological feature of many chronic autoimmune diseases, including scleroderma, rheumatoid arthritis (RA), Crohn’s disease, systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS) [ 6 , 7 ]. These fibrotic diseases have, in common, a persistent inflammatory stimulus based on lymphocyte-monocyte interactions that produce growth factors and fibrogenic cytokines, inducing the deposition of connective tissue components that progressively destroy the healthy tissue structure [ 6 , 7 ]. These data confirmed that cytokines drive the acute and chronic inflammatory responses that culminate in fibrosis activation [ 8 ].…”