NLRP3 Inflammasome and IL-11 in Systemic Sclerosis Pulmonary Fibroblasts

Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis affecting multiple organ systems. There is clinical heterogeneity among patients with SSc in terms of the organs affected. However, the pathophysiology of the disease remains elusive. The NLRP3 inflammasome is upregulated in SSc and exerts its fibrotic effects through activation of caspase-1, which in turn activates a fibrotic signaling cascade, resulting in increased collagen deposition and myofibroblast transition. Recently, IL-11 has been shown to be elevated in disease and has been shown to participate in downstream signaling via the NLRP3 inflammasome. A significant number of patients with SSc will develop pulmonary involvement, termed interstitial lung disease (SSc-ILD). Though this type of pulmonary involvement is distinct from other types of pulmonary fibrosis (such as idiopathic pulmonary fibrosis), it may be a valuable model to study mechanisms of fibrosis that could apply to other fibrotic diseases. Here, we discuss recent advances in understanding the mechanisms of the NLRP3 inflammasome and IL-11 in SSc pulmonary fibroblasts. We tie together some of the recent findings, such as senescence, the unfolded protein response, and reactive oxygen species, that contribute to fibrotic pathology via modulating NLRP3 activation, possibly leading to IL-11 expression.