Sirtuin1 Protects against Systemic Sclerosis–related Pulmonary Fibrosis by Decreasing Proinflammatory and Profibrotic Processes

Abstract

Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-α-induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-κB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-β/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.

Sirtuins and Accelerated Aging in Scleroderma

“…In some cases, the observed mechanistic effects of SIRTs are so diverse, that it is difficult to narrowly classify them [69, 88, 91, 120]. Specific intracellular signaling molecules or pathways interacting functionally with or targeted directly by SIRTs include adenosine monophosphate-activated protein kinase (AMPK) – angiotensin-converting enzyme 2 (ACE2) signaling [69, 104], peroxisome proliferator-activated receptor (PPAR)γ [97], signal transducer and activator of transcription (STAT)3 [108], mammalian target of rapamycin (mTOR) [99, 102], nuclear factor erythroid 2-related factor 2 (Nrf2) [91, 117], Krüppel-like factor (KLF)15 [110], forkhead fox O1 (FOXO1) [66] and O3 (FOXO3) [67, 68], nuclear factor κB (NF-κB) [115], Notch1 [95], matrix metalloproteinase (MMP)-14 [92], manganese superoxide dismutase (MnSOD) [65, 87], and c-Jun [13]. …”

“…At the time of preparation of this review, there are only a handful of reports that have directly addressed the involvement of SIRTs in SSc [99–102, 111, 112, 121]. Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121].…”

“…Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121]. The prevailing message from these studies is that SIRTs play an antifibrotic role in SSc and engage in mutual negative feedback with the TGF-β signaling pathway, the most potent known driver of fibrosis.…”

“…The majority of studies have shown decreased SIRT expression in tissues and fibroblasts from patients with SSc compared to controls and in experimental fibrosis in mice [99–101, 111, 112, 121]. Decreases in SIRT1 were observed in fibrotic skin and dermal fibroblasts from patients with SSc [100, 101] and in peripheral blood mononuclear cells of SSc patients with pulmonary fibrosis compared to patients without fibrosis [99].…”

“…Decreases in SIRT1 were observed in fibrotic skin and dermal fibroblasts from patients with SSc [100, 101] and in peripheral blood mononuclear cells of SSc patients with pulmonary fibrosis compared to patients without fibrosis [99]. Echoing findings in SSc skin, another group observed lower SIRT1 expression in skin tissues from patients with hypertrophic scars [103].…”