The Role of the NLRP3 Inflammasome in Fibrosis

Abstract

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.

Keywords: Caspase-1; Fibrosis; IL-18; IL-1β; NLRP3 Inflammasome; Pattern Recognition Receptors; TGF-1..

Fig. (1)

Autocrine signaling of IL-1β or IL-18 mediated by an activated inflammasome could promote myofibroblast differentiation and collagen deposition leading to fibrosis. Danger signals such as bleomycin, muramyl dipeptide, and various pathogen-related danger signals induce the assembly of the inflammasome. Once assembled the inflammasome mediates the cleavage of caspase-1 into its active form. Caspase-1 is then able to proteolytically cleave pro-IL-1β and pro-IL-18 to their mature active forms and these cytokines are secreted from the cell via a mechanism that is not fully understood. Both active IL-1β and IL-18 can autocrine signal in the fibroblast to upregulate p38 MAPK, JNK, and ERK1/2 signaling pathways resulting in increased gene expression e.g. TGF-β1 and other profibrotic genes. Active TGF-β1 is secreted from the cell and this in turn could autocrine signal to stimulate further collagen synthesis and increased α-smooth muscle actin incorporation into stress fibers that are indicative of myofibroblast differentiation.