Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr 20:14:1575-1590.
doi: 10.2147/JIR.S304180. eCollection 2021.

Inflammasome as an Effective Platform for Fibrosis Therapy

Ting-Ting Chen #  1 , Feng Xiao #  1 , Nan Li  1 , Shan Shan  1 , Meng Qi  1 , Zi-Ying Wang  1 , Sheng-Nan Zhang  1 , Wei Wei  1 , Wu-Yi Sun  1
Affiliations
Review

Inflammasome as an Effective Platform for Fibrosis Therapy

Ting-Ting Chen et al. J Inflamm Res. .

Abstract

Fibrosis is the final stage of the development of chronic inflammation. It is characterized by excessive deposition of the extracellular matrix, leading to tissue structure damage and organ dysfunction, which is a serious threat to human health and life. However, the molecular mechanism of fibrosis is still unclear. Inflammasome is a molecular complex of proteins that has been becoming a key innate sensor for host immunity and is involved in pyroptosis, pathogen infection, metabolic syndrome, cellular stress, and tumor metastasis. Inflammasome signaling and downstream cytokine responses mediated by the inflammasome have been found to play an important role in fibrosis. The inflammasome regulates the secretion of IL-1β and IL-18, which are both critical for the process of fibrosis. Recently, researches on the function of inflammasome have attracted extensive attention, and data derived from these researches have increased our understanding of the effects and regulation of inflammasome during fibrosis. In this review, we emphasize the growing evidence for both indirect and direct effects of inflammasomes in triggering fibrosis as well as potential novel targets for antifibrotic therapies.

Keywords: AIM2; NLRP3; caspase-1; fibrosis; inflammasome.

PubMed Disclaimer

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Structures of inflammasome proteins. The NLR family members include NLRP1, NLRP3, NLRC4 etc. They all contain a nucleotide-binding domain (NBD), carboxy-terminal leucine-rich repeat (LRR), and can contain either a pyrin domain (PYD) or a caspase activation and recruitment domain (CARD) or both. The AIM2 is characterized by having, in addition to a PYD, a HIN200 domain, which is involved in ligand binding. FIND, function-to-find domain.
Figure 2
Figure 2
Mechanism of NLRP3 inflammasome activation. NLRP3 inflammasome activation requires two signals to mediate both IL-1β and IL-18 production, including the priming and the activation signals. The NLRP3 inflammasome is activated by a variety of the pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The first signal activates the NF-κB pathway, leading to upregulation of pro-IL-1β, pro-IL-18 and NLRP3 protein levels. The second signal is activated in response to various stimuli (eg, K+ efflux, ROS and cathepsin B) and promotes the assembly of ASC and pro-caspase-1, leading to activation of the NLRP3 inflammasome complex. The activation drives NLRP3 inflammasome to mediate active caspase-1 production, followed by the maturation and secretion of IL-1β and IL-18. Active caspase-1 also cleaves gasdermin D (GSDMD), which allows the N-terminal domain of GSDMD to form pores in the plasma membrane. This facilitates IL-1β and-18 release and causes a lytic form of cell death (pyroptosis), which supports inflammation.
Figure 3
Figure 3
Mechanism of AIM2 inflammasome activation. AIM2 is activated by cytosolic bacteria and DNA viruses. During bacterial infection, type I interferon provides a feedback loop and activates type I interferon receptor (IFNAR). Type I interferon-signaling aids in the cytosolic access of DNA leading to the activation of AIM2. The mechanism leading to viral DNA recognition by AIM2 is less clear. The HIN-200 domain of AIM2 directly binds dsDNA, while the pyrin domain recruits ASC. Caspase-1 is recruited to ASC inflammasome to mediate pro-IL-1β and pro-IL-18 processing and induce apoptosis.
Figure 4
Figure 4
Effect and regulation of the NLRP3 inflammasome during fibrosis. Lipopolysaccharide (LPS) and other compounds induces TLR4 (toll-like receptor 4)-dependent activation of nuclear transcription factor kappa B (NF-κB), resulting in NLRP3, pro-IL-1β and pro-IL-18 expression. For instance, alcohol consumption increases permeability of the intestine to bacterial endotoxin that in turn, elevates LPS levels during alcoholic liver disease. The increase in NADPH oxidase 4 (NOX4) levels promotes mitochondrial reactive oxygen species (ROS) that leads to inflammasome activation. Thioredoxin-interacting protein (TXNIP) modulates the biological structure of NLRP3 leading to NLRP3 inflammasome assembly. Additionally, NLRP3 may damage the function of mitochondrial and induce mitochondrial ROS production, ultimately promoting NLRP3 inflammasome activation. Increased NLRP3 also involved in the transforming growth factor (TGF-β)-mediated Smad2/3 phosphorylation. IL-1β and IL-18 secreted by the inflammasome can stimulate myofibroblasts to remain activated; with the excessive extracellular matrix (ECM)-producing capacity of these cells eventually contributing to fibrosis. The mature form of IL-1β and IL-18 reaches its receptor to promote the transcription of NF-κB and increase the expression of TGF-β1. The secreted TGF-β1 binds to its receptor, triggering the Smad-dependent pathway and promoting the progression of fibrosis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Evavold CL, Kagan JC. How inflammasomes inform adaptive immunity. J Mol Biol. 2018;430(2):217–237. doi:10.1016/j.jmb.2017.09.019 - DOI - PMC - PubMed
    1. Fernandes FP, Leal VNC, Souza de Lima D, et al. Inflammasome genetics and complex diseases: a comprehensive review. Eur J Hum Genet. 2020;28(10):1307–1321. doi:10.1038/s41431-020-0631-y - DOI - PMC - PubMed
    1. Cordero MD, Alcocer-Gomez E. Editorial: inflammasome complex in health and disease: new pharmacological perspectives. Curr Drug Targets. 2017;18(9):996. doi:10.2174/1389450118666161123153230 - DOI - PubMed
    1. Artlett CM. Inflammasomes in wound healing and fibrosis. J Pathol. 2013;229(2):157–167. doi:10.1002/path.4116 - DOI - PubMed
    1. Rathinam VA, Fitzgerald KA. Inflammasome complexes: emerging mechanisms and effector functions. Cell. 2016;165(4):792–800. doi:10.1016/j.cell.2016.03.046 - DOI - PMC - PubMed

LinkOut - more resources