Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of
itaconate through diverting cis-
aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/
itaconate axis has been recently documented in
lipopolysaccharide-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 immunoresponsive gene 1/
itaconate axis exerts a modulatory effect in
ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic
brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in
ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1-/-
stroke animals exhibited exacerbated
brain injury, displayed with enlarged
cerebral infarct, compared to wild-type
stroke controls. Furthermore, IRG1-/-
stroke animals presented aggravated blood-brain barrier disruption, associated with augmented
Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1-/-
stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after
ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial
heme oxygenase-1 expression and exacerbated ischaemic
brain injury. Notably, the administration of
dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/
itaconate axis led to enhanced microglial
heme oxygenase-1 expression, alleviated ischaemic
brain injury, improved motor function and decreased mortality in IRG1-/-
stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following
ischaemic stroke serves as an endogenous protective mechanism to restrain
brain injury through
heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of
ischaemic stroke.