Succinic acid exacerbates experimental autoimmune uveitis by stimulating neutrophil extracellular traps formation via SUCNR1 receptor

Abstract

AimsTo investigate the effect of succinic acid on the development of experimental autoimmune uveitis (EAU) and the underlying mechanism.MethodsSuccinic acid was administrated intraperitoneally to evaluate its effects on immune response and EAU in mice. Intraocular inflammation was evaluated by histopathological scoring. Frequencies of Th1/Th17 cells were measured by flow cytometry. Concentrations of IFN-γ/IL-17A, neutrophil elastase (NE) and myeloperoxidase (MPO) were determined by enzyme-linked immunosorbent test. Infiltration of neutrophils and generation of neutrophil extracellular traps (NETs) within the eye were assessed by immumofluorescence. NETs formation in extracellular matrix was visualised by laser scanning confocal microscopy. Succinate receptor (SUCNR1) antagonist was used to investigate its effect on the generation of NETs.ResultsIntraperitoneal injection of succinic acid exacerbated EAU severity as evidenced by severe histological changes in association with elevated frequencies of splenic Th1/Th17 cells, and upregulated levels of IFN-γ/IL-17A and NETs in plasma. In vitro experiments showed that succinic acid could promote the generation of NETs by neutrophils as shown by increased expression of NE and MPO.NETs could increase the frequencies of Th1/Th17 cells in CD4+ T cells and their expression of IFN-γ/IL-17A. In the experiment of receptor antagonism, the upregulatory effect of succinic acid on NETs could be significantly blocked by SUCNR1 antagonist.ConclusionsSuccinic acid could worsen EAU induced by IRBP in mice. This effect was possibly mediated by its upregulation on NETs generation and frequencies of Th1/Th17 cells in affiliation with increased production of IFN-γ/IL-17A through succinic acid-SUCNR1 axis.

Intestinal Microbiomics and Metabolomics Insights into the Hepatoprotective Effects of Lactobacillus paracasei CCFM1222 Against the Acute Liver Injury in Mice

“…Succinic acid and palmitic acid serve as the intermediate products of energy metabolism, which play an antiin ammatory role in the improvement of liver injury. However, succinic acid promotes the development of autoimmune uveitis by elevating the production of IFN-γ/IL-17A and neutrophil extracellular trap generation [40]. In addition, methylglyoxal is a reactive dicarbonyl byproduct of glucose and other reducing sugars, which accumulate in mitochondria during diabetes [41].…”

Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention

“…Specifically, T cells deficient in SDHB exhibited an elevated succinate/α-KG ratio, upregulation of pro-inflammatory gene markers, and a propensity to differentiate into pro-inflammatory Th1 and Th17 lineages ( 84 ). In experimental autoimmune uveitis in mice, succinate was shown to enhance the formation of neutrophil extracellular traps and the frequencies of Th1/Th17 cells, accompanied by increased production of IFN-γ and IL-17A through the succinate-SUCNR1 axis ( 85 ). These findings highlight the pivotal roles of SDH and succinate in the adaptive immune system ( Figure 3C ).…”

Neutrophil Extracellular Traps (NETs) in Ocular Diseases: An Update

“…Uveitis mainly affects the uvea, consisting of the iris, ciliary body, and choroid, as well as the retina, vitreous, and optic nerve [ 82 ]. Some factors are involved in the development of uveitis, such as genetics, age, sex, living habits, and geographical distribution [ 83 ]. Uveitis can be classified into two categories, infectious and non-infectious.…”

“…Significantly differential metabolites have been reported to play an independent cytokine-like role in immune regulation. For example, pro-inflammatory succinic acid worsens EAU induced by retinoid-binding protein (IRBP) in mice, stimulating the formation of NETs and the frequency of Th1/Th17 cells with increased production of IFN-γ/IL-17 [ 83 , 89 , 90 ].…”