Abstract
Pulmonary fibrosis is a devastating disorder distinguished by redundant inflammation and matrix accumulation in the lung interstitium. The early inflammatory cascade coupled with recurring tissue injury orchestrates a set of events marked by perturbed matrix hemostasis, deposition of matrix proteins, and remodeling in lung tissue. Numerous investigations have corroborated a direct correlation between the NLR family pyrin domain-containing 3 (NLRP3) activation and the development of pulmonary fibrosis. Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Nevertheless, the precise mechanisms through which the NLRP3 inflammasome elicits pro-fibrogenic responses remain inadequately defined. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1β (IL-1β). IL-1β instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-β). This signaling cascade, in turn, exerts influence over various transcription factors, including SNAIL, TWIST, and zinc finger E-box-binding homeobox 1 (ZEB 1/2), which collectively foster myofibroblast activation and consequent lung fibrosis. Here, we have connected the dots to illustrate how the NLRP3 inflammasome orchestrates a multitude of signaling events, including the activation of transcription factors that facilitate myofibroblast activation and subsequent lung remodeling. In addition, we have highlighted the prominent role played by various cells in the formation of myofibroblasts, the primary culprit in lung fibrosis. We also provided a concise overview of various compounds that hold the potential to impede NLRP3 inflammasome signaling, thus offering a promising avenue for the treatment of pulmonary fibrosis.
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This work was supported by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, and National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Uttar Pradesh, India.
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Gairola, S., Sinha, A. & Kaundal, R.K. Linking NLRP3 inflammasome and pulmonary fibrosis: mechanistic insights and promising therapeutic avenues. Inflammopharmacol 32, 287–305 (2024). https://doi.org/10.1007/s10787-023-01389-5
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DOI: https://doi.org/10.1007/s10787-023-01389-5