Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Abstract

Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of IRG1/itaconate axis has recently documented in LPS-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether IRG1/itaconate axis exerts an immunomodulatory effect in ischemic stroke is unknown. Thus, we investigated whether IRG1 plays a role in modulating brain injury in ischemic stroke. In addition, the molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke were elucidated. Methods Wild type (WT) C57BL/6 and IRG1−/− mice were subjected to 40 minutes middle cerebral artery occlusion (MCAO). Ischemic brain injury, microglia (MG) activation and peripheral immune cell infiltration of the ischemic brain were assessed. Furthermore, the expression of HO-1 and BDNF in the ischemic brain was measured. Finally, IRG1−/− MCAO mice were administered with D3T, an Nrf2/HO-1 pathway inducer, to determine its effects on cerebral BDNF expression and ischemic brain injury. Results We observed IRG1 was highly induced in the ischemic brain of WT but not IRG1−/− MCAO mice. Strikingly, IRG1−/− MCAO mice exhibited exacerbated brain injury with enlarged cerebral infarct, enhanced MG activation, and elevated immune cell infiltrates compared to WT MCAO controls. Further analysis of molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke revealed that IRG1 promoted HO-1 and BDNF expression to restrain ischemic brain injury, as IRG1−/− MCAO mice exhibited reduced HO-1 and BDNF expression in the ischemic brain compared to WT MCAO controls. Notably, D3T, an Nrf2/HO-1 pathway inducer, promoted BDNF expression and lessened ischemic brain injury in IRG1−/− MCAO mice. Conclusions We demonstrate that the induction of IRG1 following ischemic stroke may serve as an endogenous protective mechanism to restrain ischemic brain injury, and that may be mediated through the protective effect of IRG1 on the induction of HO-1 and BDNF expression in the ischemic brain. Thus, our study suggests that targeting IRG1 may represent a novel approach for the treatment of ischemic stroke.

Itaconate and fumarate derivatives exert a dual inhibitory effect on canonical NLRP3 activation in macrophages and microglia

“…While mixed glia and OHSCs are useful tools to study microglial function, further studies are required to fully understand the physiological relevance of microglial metabolic reprogramming in vivo . NRF2 activation is associated with a protective effect in experimental ischaemic stroke models (Liu et al, 2019), and IRG-deficient mice exhibit exacerbated brain damage to acute ischaemic stroke, according to a recent pre-print (Kuo et al, 2020b). These studies suggest that itaconate production could be an endogenous, protective response to limit ischaemic damage.…”