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Summary: The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.