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The C3-C3aR axis modulates trained immunity in alveolar macrophages

GSE281001 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2026/08/07 Platform GPL24247
Summary
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.
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Direct links to NCBI, no account and no request form: the whole study as GSE281001_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 8 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1181815 and SRA study SRP543091. Searching any of these in the dataset finder brings you back here.

Study design
4 × WT_trained vs 4 × C3KO_trained

Supports a between-group comparison across 8 samples.

2 replicated groups read from 8 sample titles; they account for 8 of them. Check it against the sample list below before relying on it.

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