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Background <p>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory ailments globally, with the NLRP3 inflammasome playing a crucial role in the progression of ALI. G protein-coupled receptor 43 (GPR43) plays a role in regulating the immune system and maintaining homeostasis; however, the relationship between this receptor and the NLRP3 inflammasome signaling pathway in ALI is still not well understood.</p> Methods <p>Lipopolysaccharide (LPS) in combination with nigericin (Nig) was utilized to stimulate the NLRP3 inflammasome in macrophages from mouse peritoneum in vitro, after which the GPR43 selective agonist 4-CMTB was administered. For the in vivo component, an ALI model was created through intratracheal LPS injection, with the experimental group of mice receiving intraperitoneal administration of 4-CMTB at a dosage of 20&#xa0;mg/kg. Lung damage was observed as well as the activation of the NLRP3 inflammasome and pyroptosis.</p> Results <p>According to in vitro studies, 4-CMTB inhibited NLRP3 inflammasome activation, achieved by decreasing the activity of caspase-1. Additionally, it resulted in a reduction of IL-1β and IL-18 secretion, as well as decreased formation of ASC specks under LPS + Nig conditions. It also significantly inhibited the production of GSDMD-N terminus, the released lactate dehydrogenase (LDH), and the comparable ratio of propidium iodide (PI). In vivo studies showed 4-CMTB significantly alleviated the pathological damage caused by LPS in the lungs, including the infiltration of neutrophils, formation of hyaline membranes, and thickening of alveolar septa. It also lowered the lung wet/dry weight ratio and extravasation of Evans blue (EB) dye, as well as protein content of bronchoalveolar lavage fluid (BALF) and levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β). Based on the findings of the mechanistic investigation, β-arrestin 2 binding to NLRP3 was promoted by GPR43, thereby preventing the assembly and activation of the NLRP3 inflammasome.</p> Conclusion <p>GPR43 prevents NLRP3 inflammasome activation and pyroptosis by the β-arrestin 2 pathway in LPS-induced ALI. The results of the research show that we can target GPR43 to treat and cure ALI and other inflammatory diseases.</p> Clinical trial number <p>Not applicable.</p>

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GPR43 alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome activation via β-arrestin 2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Changli Wang,
  • Wangzheqi Zhang,
  • Yu Guo,
  • Yan Liao,
  • Na Li,
  • Yan Zhang,
  • Lulong Bo,
  • Jinjun Bian,
  • Jia-feng Wang

摘要

Background

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory ailments globally, with the NLRP3 inflammasome playing a crucial role in the progression of ALI. G protein-coupled receptor 43 (GPR43) plays a role in regulating the immune system and maintaining homeostasis; however, the relationship between this receptor and the NLRP3 inflammasome signaling pathway in ALI is still not well understood.

Methods

Lipopolysaccharide (LPS) in combination with nigericin (Nig) was utilized to stimulate the NLRP3 inflammasome in macrophages from mouse peritoneum in vitro, after which the GPR43 selective agonist 4-CMTB was administered. For the in vivo component, an ALI model was created through intratracheal LPS injection, with the experimental group of mice receiving intraperitoneal administration of 4-CMTB at a dosage of 20 mg/kg. Lung damage was observed as well as the activation of the NLRP3 inflammasome and pyroptosis.

Results

According to in vitro studies, 4-CMTB inhibited NLRP3 inflammasome activation, achieved by decreasing the activity of caspase-1. Additionally, it resulted in a reduction of IL-1β and IL-18 secretion, as well as decreased formation of ASC specks under LPS + Nig conditions. It also significantly inhibited the production of GSDMD-N terminus, the released lactate dehydrogenase (LDH), and the comparable ratio of propidium iodide (PI). In vivo studies showed 4-CMTB significantly alleviated the pathological damage caused by LPS in the lungs, including the infiltration of neutrophils, formation of hyaline membranes, and thickening of alveolar septa. It also lowered the lung wet/dry weight ratio and extravasation of Evans blue (EB) dye, as well as protein content of bronchoalveolar lavage fluid (BALF) and levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β). Based on the findings of the mechanistic investigation, β-arrestin 2 binding to NLRP3 was promoted by GPR43, thereby preventing the assembly and activation of the NLRP3 inflammasome.

Conclusion

GPR43 prevents NLRP3 inflammasome activation and pyroptosis by the β-arrestin 2 pathway in LPS-induced ALI. The results of the research show that we can target GPR43 to treat and cure ALI and other inflammatory diseases.

Clinical trial number

Not applicable.