Pulmonary fibrosis through the prism of NLRP3 inflammasome: mechanistic pathways and prospective therapeutic innovations

Abstract

Pulmonary fibrosis is a disease that severely affects the patients' life quality, characterized by lung tissue remodeling and functional impairment. Recent research has found that the NLRP3 inflammasome plays an important role in the pathogenesis of pulmonary fibrosis. Although existing researches have revealed the potential role of NLRP3 in pulmonary fibrosis, many mysteries still remain regarding its specific mechanisms and clinical applications. This article aims to review the mechanisms of action of NLRP3 in pulmonary fibrosis, related signaling pathways, and the latest research progress on its potential as a therapeutic target, in hopes of providing new ideas and directions for future clinical treatment.

Keywords: NLRP3 inflammasome; cellular signaling; inhibitors of NLRP3 inflammasome; pulmonary fibrosis; therapeutic strategies.

Figure 1

Regulatory mechanisms of NLRP3 inflammasome in PF. The NLRP3 inflammasome, mainly consisting of NLRP3, ASC, and pro-caspase-1, is supplied with components by the NF-κB signaling pathway. This complex can be activated in various cell types, particularly macrophages and type II alveolar epithelial cells. Activation of the inflammasome causes caspase-1 activation, leading to the maturation and release of IL-1β/IL-18 and GSDMD-mediated pyroptosis. A positive feedback loop between the NLRP3 inflammasome and NF-κB is established through IL-1β. ER stress, oxidative stress, autophagy, and metabolic changes such as glycolysis are all involved in regulating the levels of the NLRP3 inflammasome. TGF-β1 and NLRP3 inflammasome mutually enhance each other, collectively driving the progression of pulmonary fibrosis by promoting fibroblast differentiation into myofibroblasts and subsequent ECM accumulation. Figure was created with biorender.com.