Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation

Abstract

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1−/− mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs’ immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Immuno-Responsive Gene-1: A mitochondrial gene regulates pathogenic Th17 in CNS autoimmunity mouse model

“…The production of cleaved IL-1β is regulated by the cleavage of Procaspase-1 into active Caspase-1, mediated by the activated NLRP3 60 . The increased expression of IL1β in Irg1 lacking macrophages is consistent with the elevated levels of NLRP3 at both the mRNA and protein levels, as compared to Wt macrophages, suggesting that Irg1 plays a function in regulating the NLRP3 inflammasome, which is corroborated by earlier findings 41,61 . Antigen presentation and NLRP3 activation have been strongly correlated, leading to the regulation of CD4 T and CD8 T immune response 62–64 .…”