%0 Journal Article
%A Stokowska, Anna
%A Aswendt, Markus
%A Zucha, Daniel
%A Lohmann, Stephanie
%A Wieters, Frederique
%A Morán Suarez, Javier
%A Atkins, Alison L.
%A Li, YiXian
%A Miteva, Maria
%A Lewin, Julia
%A Wiedermann, Dirk
%A Diedenhofen, Michael
%A Torinsson Naluai, Åsa
%A Abaffy, Pavel
%A Valihrach, Lukas
%A Kubista, Mikael
%A Hoehn, Mathias
%A Pekny, Milos
%A Pekna, Marcela
%T Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
%J The journal of clinical investigation
%V 133
%N 10
%@ 0021-9738
%C Ann Arbor, Mich.
%I ASCJ
%M FZJ-2023-02157
%P e162253
%D 2023
%X Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR–/–) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR–/– mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 36995772
%U <Go to ISI:>//WOS:000998153000004
%R 10.1172/JCI162253
%U https://juser.fz-juelich.de/record/1007674