Pyroptosis: Mechanisms and Links with Fibrosis.

Zihao Song,Jiawei Guo,Quan Gong

doi:10.3390/cells10123509

Abstract

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1β, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1β and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.

Highlights

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden
Pyroptosis is a form of programmed cell death (PCD), characterized by cell swelling and lysis, and resulting in the release of contents and the formation of inflammation that is mediated by gasdermin (GSDM) family proteins [12,13]
In the lung injuries caused by silicon, asbestos, mechanical stretch, idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF), there is a positive correlation between inflammasomes, inflammatory cytokines and fibrosis [27,91,92,93,94]

Summary

Inflammasomes

Innate immunity is the first line of defence for detecting the presence of microbes and initiating reactions to eliminate potential threats. Most PRRs can be classified into two main classes: membrane-bound receptors and unbound intracellular receptors These receptors consist of five families based on their protein domain homology. Membranebound receptors include toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which are located on the cell surface or in endocytic compartments These receptors scan the extracellular milieu and endosomal compartments for pathogen-associated molecular patterns (PAMPs). NLRs without a CARD can interact with pro-caspase-1 to form inflammasomes with the help of apoptosis-associated speck-like proteins containing a CARD (ASC) protein, as is the case for the NLR family pyrin domain-containing 3 (NLRP3). In the presence of inflammasome activation, activated NLRP recruits PYDCARD-containing ASC proteins through a PYD–PYD interaction, and the CARD in ASCs subsequently combines with the domain of caspase-1. NLRP3 inflammasome activation in response to these conditions has been linked to the inflammation associated with the downstream release of IL-1β and IL-18 and their maturation via cleavage by caspase-1

The Mechanism of Pyroptosis

Liver Fibrosis

Lung Fibrosis

Findings

Conclusion and Perspective