In:
The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 111.02-111.02
Abstract:
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 been recently documented in lipopolysaccharide-activated mouse and human macrophages. Currently, whether IRG1/itaconate axis exerts a modulatory effect in ischemic stroke remains unexplored. In this study, we investigated whether IRG1 plays a role in modulating ischemic brain injury. Our results showed IRG1 was highly induced in the ischemic brain following ischemic injury. 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 of the ischemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86, and Iba1 expression. Further analysis revealed that IRG1 was induced in microglia after ischemic stroke, and deficiency in IRG1 resulted in repressed microglial heme oxygenase-1 (HO-1) expression. Notably, the administration of dimethyl itaconate, an itaconate derivative, to compensate the deficiency of IRG1/itaconate axis led to enhanced microglial HO-1 expression, alleviated ischemic brain injury, improved motor function, and decreased mortality rate in IRG1−/− stroke animals. In summary, we demonstrate that the induction of IRG1 in microglia following ischemic stroke may serve as a protective mechanism to restrain brain injury through HO-1 upregulation. This work was supported by Indiana University Startup Fund and in part by the National Institutes of Health (R01NS102449) to J.-H.Y.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.208.Supp.111.02
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2022
detail.hit.zdb_id:
1475085-5
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