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Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

ABSTRACT: 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.

SUBMITTER: Stokowska A

PROVIDER: S-EPMC10178843 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

Stokowska Anna A Aswendt Markus M Zucha Daniel D Lohmann Stephanie S Wieters Frederique F Morán Suarez Javier J Atkins Alison L AL Li YiXian Y Miteva Maria M Lewin Julia J Wiedermann Dirk D Diedenhofen Michael M Torinsson Naluai Åsa Å Abaffy Pavel P Valihrach Lukas L Kubista Mikael M Hoehn Mathias M Pekny Milos M Pekna Marcela M

The Journal of clinical investigation 20230515 10

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 ...[more]

PMID: 36995772

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Dataset Information

Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

Publications

Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

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