Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Cell Rep. 2021 Sep 14;36(11):109693. doi: 10.1016/j.celrep.2021.109693.
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.
损伤相关分子模式（DAMPs）引起的无菌性炎症会使缺血性中风等原发性损伤后的预后恶化。然而，目前尚无有效的治疗方法来调节 DAMPs。在这里，我们报告说，AIM（或 CD5L）蛋白通过减弱 DAMPs 来减轻无菌性炎症，并且 AIM 的给药可以改善缺血性中风的有害影响。AIM 通过基于电荷的相互作用和二硫键形成与 DAMPs 结合。这种 AIM 结合促进 DAMPs 的吞噬清除，并通过阻碍 DAMPs 与炎症受体结合来中和 DAMPs。在实验性中风中，与野生型小鼠相比，AIM 缺陷型小鼠表现出更严重的神经损伤和更高的死亡率，并且脑中 DAMPs 及其相关炎症水平更高，而中风发作后，脑内 AIM 水平增加。重组 AIM 的给药可减少梗死区域的无菌性炎症，从而显著降低动物死亡率。我们的研究结果为靶向 DAMPs 以改善缺血性中风的治疗提供了依据。
