Fibrosis is unregulated tissue repair that may cause impairment of organ function, especially in end-organ damage. Systemic sclerosis (SSc) is the prototype systemic fibrosing disorder. Classical targets for fibrosis in SSc like transforming growth factor Beta (TGF-β), Interleukin-6 (IL-6), and multiple tyrosine kinases, have not yielded therapeutic benefit. There is multitude of evidence from across different tissues like the heart, lung, skin, liver, colon, and, to some extent, the kidney, that interleukin-17 (IL-17) and its downstream pathways are strongly associated with the initiation and propagation of fibrosis. Data from scleroderma patients, as well as from animal models of SSc, mirror these findings. Interestingly, hitherto unknown to be related to IL-17, newer molecules like Programmed Death-protein1 (PD-1), the phosphatase SHP2, along with known signal transducers like signal transducer and activator of transcription (STAT3), have been recently shown to be involved in the pathogenesis of fibrosis. Related molecules include the intracellular signalling molecules Ras/Erk, mammalian target organ of rapamycin (mTOR), and complement components. The biology of these pathways has not yet been fully elucidated to predict regulatory mechanisms, redundancies, and potential off-target effects. All these need to be better understood in the context of each other, in an effort to arrive at the optimal target to modulate fibrosis.
Keywords: Fibrosis; Interleukin 17; STAT3; Systemic sclerosis; T helper 17.