The complement C3‐C3aR pathway mediates microglia–astrocyte interaction following status epilepticus

Abstract

Gliosis is a histopathological characteristic of epilepsy that comprises activated microglia and astrocytes. It is unclear whether or how crosstalk occurs between microglia and astrocytes in the evolution of epilepsy. Here, we report in a mouse model of status epilepticus, induced by intracerebroventricular injection of kainic acid (KA), sequential activation of microglia and astrocytes and their close spatial interaction in the hippocampal CA3 region. Microglial ablation reduced astrocyte activation and their upregulation of complement C3. When compared to wild‐type mice, both C3−/− and C3aR−/− mice had significantly less microglia–astrocyte interaction in response to KA‐induced status epilepticus. Additionally, KA‐injected C3−/− mice had significantly less histochemical evidence of neurodegeneration. The results suggest that the C3‐C3aR pathway contributes to KA‐induced neurodegeneration by mediating microglia–astrocyte communication. The C3‐C3aR pathway may prove to be a potential therapeutic target for epilepsy treatment.

Suppression of Microgliosis With the Colony-Stimulating Factor 1 Receptor Inhibitor PLX3397 Does Not Attenuate Memory Defects During Epileptogenesis in the Rat

“…This finding further supports that these two cell types communicate which each other under pathological conditions (50). Microglia and astrocytes communicate through a number of molecules including complement proteins (32,50), which are upregulated in epilepsy (9). Reactive microglia produce and release the complement protein C1q which in turn triggers astrocytes to release C3a which then binds to its receptor (C3aR) in astrocytes, thereby producing a regulatory loop (32,50).…”

“…Although PLX3397 reduced astrogliosis, the levels of C3 protein in whole hippocampal homogenates remained unchanged. This suggests the possibility that other pathways or cell types may be regulating C3 levels in response to SE, or that the immunoblot approach used in our study missed changes that may be regional within the hippocampal formation, as recently shown by Wei et al (32). Furthermore, due to the tight association between SE-induced increases in C3 complement activation and memory decline following pilocarpine-induced SE in rats (5,6) we speculate that the high levels of C3 still present in both SE groups (PLX3397 and standard chow) may be modulating the memory loss.…”

“…To further assess the effects of PLX treatment on microglia we determined levels of the CX3C chemokine receptor 1 (CX3CR1) which is expressed in microglia ( 29 , 30 ). In parallel, we determined levels of the complement protein C3 and its biologically active fractions because these are produced/released by astrocytes in response to microglial signals ( 31 , 32 ) and are increased by SE ( 5 , 6 , 32 ). We found significantly increased levels of CX3CR1 protein in hippocampi of SE+SC rats when compared to the C+SC group [ Figure 7B , main effect condition, two-way ANOVA, F (1,42) = 17.97, p = 0.0001] (C+SC vs. SE+SC, p = 0.001).…”

Neuroinflammation as a Therapeutic Target for Mitigating the Long-Term Consequences of Acute Organophosphate Intoxication

“…Thus, in situations with robust and potentially shifting profiles of microglial activation, it is likely that the functional polarization of microglia critically influences the functional polarization of astrocytes, and ultimately, the general direction of the neuroinflammatory response following acute OP intoxication. Indeed, there is evidence that neurotoxic C3-positive astrocyte polarization develops by 3 days after kainate- or DFP-induced SE ( Wei et al, 2020 ; Maupu et al, 2021 ) and remains elevated at 6 weeks post intoxication ( Putra et al, 2020 ). Importantly, this astrocytic polarization was dependent on microglial function ( Wei et al, 2020 ), suggesting that microglia promoted the delayed development of neurotoxic astrocytes following acute OP intoxication.…”

“…Indeed, there is evidence that neurotoxic C3-positive astrocyte polarization develops by 3 days after kainate- or DFP-induced SE ( Wei et al, 2020 ; Maupu et al, 2021 ) and remains elevated at 6 weeks post intoxication ( Putra et al, 2020 ). Importantly, this astrocytic polarization was dependent on microglial function ( Wei et al, 2020 ), suggesting that microglia promoted the delayed development of neurotoxic astrocytes following acute OP intoxication.…”