Role of cellular senescence in the pathogenesis of systemic sclerosis

Abstract

Purpose of reviewSystemic sclerosis (SSc) is a chronic rheumatic disease that is characterized by immune activation, vasculopathy and fibrosis of the skin and internal organs. It has been proposed that premature onset of ageing pathways and associated senescent changes in cells contribute to the clinical and pathological features of SSc. The aim of this review is to critically review recent insights into the involvement of cellular senescence in SSc.Recent findingsCellular senescence plays a critical role in SSc pathogenesis, particularly involving endothelial cells and fibroblasts. Immunosenescence could also contribute to SSc pathogenesis by direct alteration of cellular functions or indirect promotion of defective immune surveillance. Molecular studies have shed some light on how cellular senescence contributes to fibrosis. Recent and planned proof-of-concept trials using senotherapeutics showed promising results in fibrotic diseases, including SSc.SummaryThere is increasing evidence implicating cellular senescence in SSc. The mechanisms underlying premature cellular senescence in SSc, and its potential role in pathogenesis, merit further investigation. Emerging drugs targeting senescence-related pathways might be potential therapeutic options for SSc.

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

“…The age-related diseases are progressive disorders which commonly involve both inflammatory changes and fibrotic degeneration. Typically, these diseases also are associated with the accumulation of senescent cells with inflammatory and degenerative changes, such as in atherosclerosis, chronic obstructive lung disease (COPD), coronary artery disease (CAD), and Alzheimer’s disease (AD) [ 70 – 73 ] as well as in fibrotic diseases, e.g., in idiopathic pulmonary disease (IPF), cardiac fibrosis, and systemic sclerosis [ 70 , 74 , 75 ]. There exists a significant crosstalk between senescent cells and inflammatory cells in the pathogenesis of many age-related diseases, e.g., via the control of the expression of inhibitory checkpoint proteins.…”

The contribution of endothelial cells to tissue fibrosis

“…Apart from directly transdifferentiating into myofibroblasts, endothelial cells may contribute to tissue fibrosis also in different indirect ways comprising the acquisition of a senescent phenotype and the release of exosomes and a variety of profibrotic/ proinflammatory mediators, with consequent recruitment of inflammatory/immune cells that further boost the fibrotic process [1,[68][69][70].…”

“…Senescent cells are cell cycle arrested cells characterized by morphological and metabolic changes, chromatin reorganization, and altered gene expression [ 68 , 69 ]. Indeed, they display heterogeneous markers of senescence such as the proliferation inhibitors p16INK4A, p21, or p53, and a proinflammatory secretory phenotype, known as SASP, encompassing a variety of biologically active mediators, including growth factors and cytokines (e.g., TGF-β, TNF-α, IL-1β, and IL-6), chemokines, ECM proteins, and enzymes (e.g., MMPs) [ 68 , 69 ]. Through these secreted factors, senescent cells signal in both autocrine and paracrine ways, likely inducing senescence in neighboring cells and allowing senescence to spread [ 68 , 69 ].…”

“…Indeed, they display heterogeneous markers of senescence such as the proliferation inhibitors p16INK4A, p21, or p53, and a proinflammatory secretory phenotype, known as SASP, encompassing a variety of biologically active mediators, including growth factors and cytokines (e.g., TGF-β, TNF-α, IL-1β, and IL-6), chemokines, ECM proteins, and enzymes (e.g., MMPs) [ 68 , 69 ]. Through these secreted factors, senescent cells signal in both autocrine and paracrine ways, likely inducing senescence in neighboring cells and allowing senescence to spread [ 68 , 69 ]. Programmed cellular senescence seems to be an apoptosis-like transient biological mechanism that can be exploited to eliminate unwanted cells, as the inflammatory SASP leads to the recruitment of immune cells with consequent cell clearance.…”

Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches

“…2) [25,26 ▪▪ ]. Increasing evidence indicates that patients with SSc display features of accelerated ageing, with premature accumulation of senescent cell and up-regulation of senescence-associated pathways [27]. Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in cellular senescence-associated conditions including atherosclerosis, liver cirrhosis, osteoarthritis, diabetes and idiopathic pulmonary fibrosis [28].…”