Sirt5-mediated polarization and metabolic reprogramming of macrophage sustain brain function following ischemic stroke

Ischemic stroke has become the leading cause of morbidity and mortality in adults. Reperfusion may initiate inflammatory response and cause damage to brain. Macrophage is supposed to be the major contributor of neuroinflammation and immune response. Hypersuccinylation correlates with neuropathological process post cerebral ischemia, rendering the possibility of functional role of succinylation in regulating recovery from injury. Here we reported that ischemic stroke causes upregulation of global protein succinylation dramatically. Mechanically, Sirt5 expression is repressed upon ischemic stroke, which exerts a crucial role in orchestrating global protein succinylation level. Furthermore, deficiency of Sirt5 enhances infiltration, M1 polarization and metabolic programming of macrophage in response to stroke via succinylation of Pkm2. Physiologically, depletion of Sirt5 enlarges damage region of brain during stroke. Utilization of Sirt5 agonist resveratrol efficiently ameliorates the destructive effects induced by stroke, thereby supporting recovery from brain injury. Our study not only reveal a heretofore unrecognized mechanism underlying the relation between stroke and protein succinylation, but also shed light on clinical potential for management of stroke injury via targeting protein succinylation.