Objective: Systemic sclerosis (SSc) is a chronic idiopathic disease of unknown etiology that is characterized by fibrosis of the skin and visceral organs mediated by activated myofibroblasts. The recently identified inflammasomes are cytosolic receptors that tightly regulate the activity of caspase 1 and downstream signaling molecules such as interleukin‐1β (IL‐1β) and IL‐18. The nucleotide‐binding oligomerization domain (NOD)–like receptor 3 (NLRP3) inflammasome has been implicated in the development of idiopathic pulmonary fibrosis. This study was undertaken to assess the role of the inflammasome in SSc‐related dermal or pulmonary fibrosis.Methods: Inflammasome gene transcripts were assayed in fibroblasts obtained from patients with SSc. Caspase 1 activation in SSc primary dermal and lung fibroblasts was inhibited, and the levels of hydroxyproline, COL1A1, COL3A1, IL‐1β, IL‐18, and α‐smooth muscle actin (α‐SMA) were measured. The role of the inflammasome in dermal fibrosis was investigated in NLRP3^−/− and ASC^−/− mice.Results: We identified increased expression of 40 genes associated with the inflammasome or downstream signaling molecules in SSc fibroblasts. Inhibition of caspase 1 in SSc dermal and lung fibroblasts abrogated the secretion of collagens, IL‐1β, and IL‐18. In addition, we observed decreased expression of the myofibroblast protein α‐SMA in SSc dermal fibroblasts treated with a caspase 1 inhibitor. Furthermore, NLRP3^−/− mice and ASC^−/− mice were resistant to bleomycin‐induced skin fibrosis, which suggests a key role for the inflammasome in in vivo fibrosis.Conclusion: Innate immune signaling contributes to SSc fibrosis via activation of the inflammasome and caspase 1. These results suggest that inflammasome activation may play an important role in the pathogenesis of SSc.

Despite the important role that microRNAs (miRNAs) play in immunity and inflammation, their involvement in systemic sclerosis (SSc) remains poorly characterized. miRNA-155 (miR-155) plays a role in pulmonary fibrosis and its expression can be induced with interleukin (IL)-1β. SSc fibroblasts have activated inflammasomes that are integrally involved in mediating the myofibroblast phenotype. In light of this, we investigated whether miR-155 played a role in SSc and if its expression was dependent on inflammasome activation. miR-155 expression was confirmed in SSc dermal and lung fibroblasts by quantitative polymerase chain reaction (PCR). Wild-type and NLRP3-deficient murine fibroblasts were utilized to explore the regulation of miR-155 during inflammasome activation. miR-155-deficient fibroblasts and retroviral transductions with a miR-155 expression or control vectors were used to understand the contribution of miR-155 in fibrosis. miR-155 was significantly increased and the highest expressing miRNA in SSc lung fibroblasts. Its expression was dependent on inflammasome activation as miR-155 expression could be blocked when inflammasome signaling was inhibited. In the absence of miR-155, inflammasome-mediated collagen synthesis could not be induced but was restored when miR-155 was expressed in miR-155-deficient fibroblasts. miR-155 is upregulated in SSc. These results suggest that the inflammasome promotes the expression of miR-155 and that miR-155 is a critical miRNA that drives fibrosis.

Fibrosis leads to the deposition of collagens in organs and tissues. The resulting pathology induces a loss of function in the organ it is manifested in and this loss of function modulates the morbidity and mortality in that individual. Indeed, approximately 45% of all deaths in the Western world can be attributed to fibrosis and there are no FDA approved drugs for the treatment of fibrosis. The recent discovery of the inflammasome has led to a plethora of studies investigating this inflammatory signaling pathway in a wide variety of pathogen associated diseases. Many studies have focused on the NLRP3 inflammasome and this inflammasome is activated by a wide variety of cellular alarm signals. Once activated, caspase-1 is cleaved, inducing the secretion of IL-1β and IL-18 that signal to aid in the clearance of invading organisms. However, as the knowledge of the inflammasome has expanded, it was found that it can directly control collagen synthesis, leading to the increased deposition of collagens in the tissues such as the lung, liver, heart, and skin. Mice lacking the inflammasome adaptor protein, ASC, failed to become fibrotic when exposed to bleomycin. Inhibition of caspase-1 activity in fibroblasts from patients with the fibrotic disease systemic sclerosis, decreased collagen synthesis and reduced α-smooth muscle actin expression in myofibroblasts. Taken together, these observations suggest that the inflammasome can drive the fibrotic response and paves the way for novel therapeutics to be identified.

Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations in the tissue, causing permanent damage and organ dysfunction. Depending on the organ it effects, fibrosis can be a serious threat to human life. The molecular mechanism of fibrosis is still not fully understood, but the NLRP3 (NOD-, LRR- and pyrin–domain–containing protein 3) inflammasome appears to play a significant role in the pathogenesis of fibrotic disease. The NLRP3 inflammasome has been the most extensively studied inflammatory pathway to date. It is a crucial component of the innate immune system, and its activation mediates the secretion of interleukin (IL)-1β and IL-18. NLRP3 activation has been strongly linked with fibrosis and drives the differentiation of fibroblasts into myofibroblasts by the chronic upregulation of IL-1β and IL-18 and subsequent autocrine signaling that maintains an activated inflammasome. Both IL-1β and IL-18 are profibrotic, however IL-1β can have antifibrotic capabilities. NLRP3 responds to a plethora of different signals that have a common but unidentified unifying trigger. Even after 20 years of extensive investigation, regulation of the NLRP3 inflammasome is still not completely understood. However, what is known about NLRP3 is that its regulation and activation is complex and not only driven by various activators but controlled by numerous post-translational modifications. More recently, there has been an intensive attempt to discover NLRP3 inhibitors to treat chronic diseases. This review addresses the role of the NLRP3 inflammasome in fibrotic disorders across many different tissues. It discusses the relationships of various NLRP3 activators to fibrosis and covers different therapeutics that have been developed, or are currently in development, that directly target NLRP3 or its downstream products as treatments for fibrotic disorders.

The function of microRNAs (miRNAs) during fibrosis and the downstream regulation of gene expression by these miRNAs have become of great biological interest. miR-155 is consistently upregulated in fibrotic disorders, and its ablation downregulates collagen synthesis. Studies demonstrate the integral role of miR-155 in fibrosis, as it mediates TGF-β1 signaling to drive collagen synthesis. In this review, we summarize recent findings on the association between miR-155 and fibrotic disorders. We discuss the cross-signaling between macrophages and fibroblasts that orchestrates the upregulation of collagen synthesis mediated by miR-155. As miR-155 is involved in the activation of the innate and adaptive immune systems, specific targeting of miR-155 in pathologic cells that make excessive collagen could be a viable option before the depletion of miR-155 becomes an attractive antifibrotic approach.