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 6

Intranasal C3a modulates post-stroke cortical connectivity.

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Intranasal C3a modulates post-stroke cortical connectivity. (A) Study de...
(A) Study design. (B) 3D illustration of T2-weighted MRI (T2w-MRI) with the infarct (in red) and stroke incidence maps of PBS- and C3a-treated mice. (C) Infarct location based on quantitative lesion mapping using T2w-MRI: primary somatosensory area (SSp) upper limb (SSp-ul), lower limb (SSp-ll), nose (SSp-n), mouth (SSp-m), barrel field (SSp-bfd), unassigned (SSp-un); primary and secondary motor area (MOp and MOs). (D) Infarct volume based on quantitative lesion mapping using T2w-MRI on P7. (E) Regions selected for fiber tracking analysis. (F and G) Number of fibers from ipsilesional MOp (F) and SSp-ul (G) to the most strongly connected regions before stroke (BL) and on P7. (H and I) Number of fibers from ipsilesional MOp (H) and supplemental somatosensory area (SSs) (I) to primary somatosensory cortex before stroke (BL) and on P56. (J) DTI global density (ratio of connections to the maximum possible number of connections for all 96 brain regions) before stroke (BL) and on P7, P28, and P56. (K and L) Recovery of motor function as assessed by change in the frequency of foot faults in the grid walk test (K) and paw drags per touch in the cylinder test (L) between P7 and P56. (M) Representative images of ipsilesional motor cortex of PBS- and C3a-treated mice in which astrocytes are visualized with antibodies against GFAP on P56. Scale bar: 100 μm. Relative GFAP-positive area in proximal peri-infarct and contralesional cortex of PBS- and C3a-treated mice (P56). PBS, n = 7; C3a, n = 10. Bar plots represent mean ± SEM. Two-way mixed effects analysis with false discovery rate correction (F–J); 2-way mixed effects analysis with Šidák’s corrections (K and L); 2-way ANOVA with Šidák’s planned comparisons (M); *P < 0.05, **P < 0.01, ***P < 0.001 for comparison between time points or ipsilesional vs. contralesional; #P < 0.05, ##P < 0.01, ###P < 0.001 for between-treatment comparison.