Zoledronic acid attenuates ischemic brain injury by promoting ETS2 and MSR1 expression

Abstract Intracerebral inflammation and brain swelling often worsen the functional prognosis of stroke patients. Post-stroke inflammation is resolved by the removal of inflammatogenic damage-associated molecular patterns (DAMPs) through macrophage scavenger receptor 1 (MSR1); however, therapeutics promoting MSR1 expression efficiently have not been developed. We identified ETS2 as a transcription factor that promoted MSR1 expression in myeloid cells by epigenetic molecular screening. Increased Ets2 expression in macrophages enhanced MSR1 expression and the internalization of peroxiredoxins (PRXs), pivotal inflammatogenic DAMPs in ischemic stroke. By evaluation of chemicals inducing Ets2 expression, we discovered that zoledronic acid increased Ets2 and Msr1 expression in macrophages. Post-stroke administration of zoledronic acid significantly suppressed cerebral inflammation by increasing MSR1 expression in infiltrating myeloid cells, attenuating ischemic neuronal injury in a myeloid Ets2-dependent manner. Thus, epigenetic molecular screening that enhances MSR1 expression is a useful approach to developing therapeutics that improve functional prognosis after ischemic stroke.