AIM/CD5L attenuates DAMPs in the injured brain and thereby ameliorates ischemic stroke
Natsumi Maehara,
Kaori Taniguchi,
Ami Okuno,
Hideaki Ando,
Aika Hirota,
Zhiheng Li,
Ching-Ting Wang,
Satoko Arai,
Toru Miyazaki
Affiliations
Natsumi Maehara
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Kaori Taniguchi
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Ami Okuno
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Hideaki Ando
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Aika Hirota
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Zhiheng Li
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Ching-Ting Wang
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Satoko Arai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Corresponding author
Toru Miyazaki
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; LEAP, Japan Agency for Medical Research and Development, Tokyo 113-0033, Japan; Laboratoire d’ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France; Corresponding author
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.
