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 4

Intranasal C3a does not affect the density of microglia in peri-infarct cortex.

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Intranasal C3a does not affect the density of microglia in peri-infarct ...
(A and B) Representative images of contralesional and ipsilesional cortex stained with antibodies against Iba-1 on P21 (A) and P56 (B). Cortical regions were chosen for analysis as shown in Figure 3D. Scale bars: 100 μm. (C and D) Density of Iba-1–positive cells in the proximal peri-infarct and contralesional cortex of mice treated with PBS or C3a on P21 (C) or P56 (D). PBS, n = 8–9; C3a, n = 9–10. (E and F) Representative images of contralesional and ipsilesional motor cortex stained with antibodies against Iba-1 and Clec7a on P14 (E) and P28 (F). Cortical regions were chosen for analysis as shown in Figure 3D. Scale bars: 100 μm. (G and H) Density of Clec7a-positive cells in the proximal peri-infarct and contralesional cortex of mice treated with PBS or C3a on P14 (G) or P28 (H). P14: PBS, n = 6; C3a, n = 6. P28: PBS, n = 10; C3a, n = 10. Bar plots represent mean ± SEM. Contra, contralesional; ipsi, ipsilesional; M, motor cortex; S, somatosensory cortex. Two-way ANOVA with Šidák’s planned comparisons: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 for ipsilesional vs. contralesional comparisons.