Cell Reports ( IF 8.8 ) Pub Date : 2021-09-14 , DOI: 10.1016/j.celrep.2021.109693 Natsumi Maehara 1 , Kaori Taniguchi 1 , Ami Okuno 1 , Hideaki Ando 1 , Aika Hirota 1 , Zhiheng Li 1 , Ching-Ting Wang 1 , Satoko Arai 1 , Toru Miyazaki 2
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.
中文翻译:
AIM/CD5L 减弱受损大脑中的 DAMP,从而改善缺血性中风
由损伤相关分子模式 (DAMP) 引起的无菌炎症会恶化原发性损伤(如缺血性中风)后的预后。然而,没有有效的治疗方法来调节 DAMP。在这里,我们报告了 AIM(或 CD5L)蛋白通过减弱 DAMP 来减少无菌性炎症,并且 AIM 给药改善了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 DAMP 结合。这种 AIM 关联促进了 DAMP 的吞噬清除,并通过阻止 DAMP 与炎症受体的结合来中和 DAMP。在实验性中风中,与野生型小鼠相比,AIM 缺陷型小鼠表现出严重的神经损伤和更高的死亡率,大脑中 DAMP 和相关炎症水平更高,其中脑 AIM 水平在中风发作后增加。重组 AIM 给药可减少梗塞区域的无菌炎症,从而显着降低动物死亡率。我们的研究结果为针对 DAMP 改善缺血性中风的疗法提供了基础。