Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
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
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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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 2

Overexpression of C3a reduces astrocyte reactivity but increases microglia density in peri-infarct cortex.

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Overexpression of C3a reduces astrocyte reactivity but increases microgl...
(A) Representative images of ipsilesional and contralesional cortex of WT and GFAP-C3a mice in which astrocytes are visualized with antibodies against GFAP on P21. Scale bar: 100 μm. (B) Relative GFAP-positive area in proximal peri-infarct and contralesional cortex. WT, n = 9; GFAP-C3a, n = 9. Contra, contralesional; ipsi, ipsilesional; M, motor cortex; S, somatosensory cortex. Regions for analysis were chosen as shown in Figure 1B. (C) Representative images of ipsilesional and contralesional cortex of WT and GFAP-C3a mice stained with antibodies against Iba-1 on P21. Scale bar: 100 μm. (D) Density of Iba-1–positive cells in proximal peri-infarct and contralesional cortex. WT, n = 9; GFAP-C3a, n = 9. Regions for analysis were chosen as shown in Figure 1D. (E–G) Recovery of motor function of WT (n = 13) and GFAP-C3a (n = 12) mice assessed by changes in distance walked in the beam test between P2 and P7 (E), P7 and P14 (F), and P14 and P21 (G). Bar plots represent mean ± SEM. Two-way ANOVA with Šidák’s planned comparisons (B and D): *P < 0.05, ***P < 0.001, ****P < 0.0001 for ipsilesional vs. contralesional comparisons; #P < 0.05, ##P < 0.01, ###P < 0.001 for between-genotype comparisons. Two-way ANOVA with repeated measures and Šidák’s planned comparisons (E and G): *P < 0.05.