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The C3-C3aR axis modulates trained immunity in alveolar macrophages

ABSTRACT: Complement protein C3 is crucial for immune responses in mucosal sites like the respiratory system, where it aids in microbe elimination and enhances inflammation. While trained immunity – enhanced secondary responses of innate immune cells after prior exposure – is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs – a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE281001 | GEO | 2026/08/07

REPOSITORIES: GEO

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