Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
Anna Stokowska, … , Milos Pekny, Marcela Pekna
Anna Stokowska, … , Milos Pekny, Marcela Pekna
Published March 30, 2023
Citation Information: J Clin Invest. 2023;133(10):e162253. https://doi.org/10.1172/JCI162253.
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Research Article Neuroscience

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.

Authors

Anna Stokowska, Markus Aswendt, Daniel Zucha, Stephanie Lohmann, Frederique Wieters, Javier Morán Suarez, Alison L. Atkins, YiXian Li, Maria Miteva, Julia Lewin, Dirk Wiedermann, Michael Diedenhofen, Åsa Torinsson Naluai, Pavel Abaffy, Lukas Valihrach, Mikael Kubista, Mathias Hoehn, Milos Pekny, Marcela Pekna

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Figure 3

Intranasal C3a reduces astrocyte reactivity in peri-infarct cortex.

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Intranasal C3a reduces astrocyte reactivity in peri-infarct cortex. (A) ...
(A) Study design. (B and C) Representative images of ipsilesional and contralesional cortex of mice treated with PBS or C3a. Astrocytes were visualized with antibodies against GFAP on P21 (B) and P56 (C). Scale bars: 100 μm. (D) Schematic of cortical regions chosen for analysis. Ctx, cortex; CC, corpus callosum; Str, striatum; ipsi, ipsilesional; M, motor cortex; S, somatosensory cortex. (E and F) Relative GFAP-positive area in proximal peri-infarct and contralesional cortex of mice treated with PBS or C3a on P21 (E) or P56 (F). PBS, n = 9; C3a, n = 8–9. (G) Association between GFAP expression in ipsilesional motor cortex on P56 and improvement in grid walk test, defined as the difference in percentage of right (affected) front paw foot faults, between P7 and P56. r, Pearson’s correlation coefficient; rho, Spearman’s correlation coefficient. Line represents the linear regression fit. Bar plots represent mean ± SEM. Two-way ANOVA with Šidák’s planned comparisons: **P < 0.01, ***P < 0.001, ****P < 0.0001 for ipsilesional vs. contralesional comparisons; ##P < 0.01, ###P < 0.001 for between-treatment comparisons.