Treatment of silicosis with quercetin depolarizing macrophages via inhibition of mitochondrial damage-associated pyroptosis.

Ecotoxicol Environ Saf

Department of Pulmonary and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China; Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China. Electronic address:

Published: November 2024

AI Article Synopsis

  • The study investigates how silica exposure causes macrophages to polarize towards a pro-inflammatory state (M1 polarization) through mechanisms involving mitochondrial damage and pyroptosis.
  • Quercetin (Que) is evaluated as a potential treatment that can reverse this polarization and mitigate associated lung inflammation and fibrosis.
  • The findings suggest that Que binds to TOM70, helping to restore mitochondrial function and reduce macrophage-driven inflammatory responses, which could lead to new therapeutic strategies for treating silicosis.

Article Abstract

Macrophage polarization facilitates the inflammatory response and intensified fibrosis in the silicosis microenvironment by a mechanism related to macrophage pyroptosis, although the upstream target remains poorly defined. Currently, there are few reports on the development of drugs that alleviate macrophage polarization by dampening pyroptosis. The present study aims to explore the mechanics of silica mediating macrophage polarization and to investigate whether quercetin (Que) can depolarize macrophages with this mechanism. Silica processing led to prominent M1 polarization of macrophages. Additionally, significant macrophage polarization could be detected in the lung tissue of mice with airway-perfused silica. Further investigation turned out that pronounced mitochondria damage, mtDNA cytoplasmic ectomy, and pyroptosis occurred in response to silica. Nevertheless, Que treatment could effectively attenuate silica-induced mitochondria damage and pyroptosis as demonstrated in vitro and in vivo. Further exploration presented Que could bind to TOM70 and restore silica-induced mitochondrial damage. More importantly, the M1 polarization of macrophage was depressed with the co-treatment of Que and silica, wherein the inflammatory response and pulmonary fibrosis were also mitigated without obvious damage to vital organs. In conclusion, these findings proved that silica leads to mitochondrial damage, thereby evoking pyroptosis and promoting macrophage M1 polarization. Que could bind to TOM70 and restore its function, suppressing mitochondrial damage and pyroptosis, and depolarizing macrophages to reduce fibrosis, which provides a promising strategy for silicosis treatment in the future.

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Source
http://dx.doi.org/10.1016/j.ecoenv.2024.117161DOI Listing

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