Annexin A1 inhibition facilitates NLRP3 inflammasome activation in arsenic-induced insulin resistance in rat liver

Environ Toxicol Pharmacol. 2022 Nov:96:103981. doi: 10.1016/j.etap.2022.103981. Epub 2022 Sep 28.

Abstract

Hepatic insulin resistance (IR) is the primary pathology of type 2 diabetes (T2D). The role of the NOD-like receptor protein 3 (NLRP3) inflammasome in arsenic-induced hepatic IR has been previously demonstrated. However, the mechanism of the arsenic-induced activation of the NLRP3 inflammasome is still unclear. Here, we demonstrate that NaAsO2 downregulated the mRNA and protein level of Annexin A1 (AnxA1), an anti-inflammatory factor, in rat livers and L-02 cells. Moreover, AnxA1 overexpression significantly alleviated arsenic-induced NLRP3 inflammasome activation and IR in L-02 cells. Importantly, Co-immunoprecipitation (Co-IP) results showed that AnxA1 1-190 peptide could bind to the domain encompassing amino acids 1-210 and 211-550 of NLRP3. In conclusion, our experiments demonstrated that arsenic exposure could activate the NLRP3 inflammasome and IR by inhibiting the AnxA1 activity. These findings suggest that AnxA1 may be a promising therapeutic target of arsenicosis.

Keywords: Annexin A1; Arsenic; Insulin resistance; NLRP3; Type 2 diabetes.

MeSH terms

  • Animals
  • Annexin A1* / genetics
  • Annexin A1* / metabolism
  • Arsenic* / metabolism
  • Arsenic* / toxicity
  • Diabetes Mellitus, Type 2* / metabolism
  • Inflammasomes / metabolism
  • Insulin Resistance*
  • Liver / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • NLR Proteins / metabolism
  • Rats

Substances

  • Annexin A1
  • Arsenic
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • Nlrp3 protein, rat