Pulmonary succinate receptor 1 elevation in high-fat diet mice exacerbates lipopolysaccharides-induced acute lung injury via sensing succinate

Background: Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and Succinate Receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI).

Methods: The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 μg, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated.

Result: The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1α (HIF-1α) expression, inhibitory κB-α (IκB-α) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1α expression and IκB-α phosphorylation.

Conclusion: The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury.

Acute lung injury; Lipopolysaccharides; Obesity; Succinate; Succinate receptor 1.