The Complex Role of the Complement C3a Receptor (C3aR) in Cerebral Injury and Recovery Following Ischemic Stroke

Document Type

Article

Abstract

The Complement C3a Receptor (C3aR) plays a multifaceted role along the varying temporal phases of brain injury following cerebral ischemia. C3aR is a G-protein-coupled receptor (GPCR) that binds to its ligand, C3a an anaphylatoxin generated during activation of the complement cascade. During ischemia, complement is activated as part of the initial inflammatory response, with C3aRs playing a time-dependent role in both brain injury and repair mechanisms. In the acute phase (minutes to hours post-ischemia), C3aR activation promotes the recruitment of immune cells and the release of chemokines and cytokines, driving blood-brain barrier (BBB) permeability and brain edema. During the subacute phase (hours to days post-ischemia), C3aR continues to modulate immune cell activity, worsening secondary brain injury, although emerging evidence suggests that C3aR activation in this phase may also aid in the clearance of cellular debris and cell survival. In the chronic phase (days to weeks post-ischemia), chronically elevated C3aR activity can prolong neuroinflammation and impair recovery, whereas controlled C3aR signaling in the subacute/chronic phase can activate reparative pathways (e.g., microglial phagocytosis, astrocyte trophic support). As a result, targeting the C3aR requires careful timing to optimize its benefits. Given the dual impact of C3aR activation, which serves to exacerbate injury in the acute phase but supports repair beginning in the subacute and chronic phases, a targeted therapeutic approach should focus on context- and time-dependent modulation of the C3a/C3aR axis. This strategy would involve blocking the C3aR during the acute phase to reduce inflammation and BBB breakdown while controlling C3a signaling in later phases to promote tissue repair.

Keywords

complement C3a receptor (C3aR), ischemic stroke, neuroinflammation, temporal phases of brain injury, therapeutic modulation

Medical Subject Headings

Humans; Receptors, Complement (metabolism); Animals; Ischemic Stroke (metabolism, pathology); Blood-Brain Barrier (metabolism); Brain Injuries (metabolism); Complement C3a (metabolism); Signal Transduction

Publication Date

9-15-2025

Publication Title

Cells

E-ISSN

2073-4409

Volume

14

Issue

18

PubMed ID

41002405

Digital Object Identifier (DOI)

10.3390/cells14181440

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