Macrophages are central to host defence, eliminating pathogens and orchestrating inflammation, an immune response which must be tightly regulated to prevent collateral tissue damage. Colony-stimulating factor 1 receptor (CSF1R) is a key regulator of macrophage differentiation, survival, and proliferation. In humans’ mutations in CSF1R have been identified and linked to neurodegenerative disease. However, it remains unclear if individuals carrying these mutations experience altered outcomes during acute or chronic intracellular macrophage infections. To address this, we investigate the role of CSF1R signalling in acute Listeria monocytogenes (Lm) and chronic Mycobacterium bovis (BCG) infection using a mouse model with a point mutation in Csf1r that mirrors a human amino acid substitution in the kinase domain of CSF1R, severely blunting signalling in heterozygous Csf1r-E631K mice.
Wildtype (WT/WT) and Csf1r-E631K (WT/mut) mice were infected intravenously with Lm (3x103 CFU) or BCG (3.5x105 CFU). Bacterial burden, immune composition, gene expression, and histopathology were assessed at 3- and 10-days post infection (d.p.i.) for Lm and at 3-, 8-, and 16-weeks post infection (w.p.i.) for BCG.
Across both models, bacterial burdens in the liver and spleen were comparable between genotypes at all timepoints. Both genotypes cleared Lm 10 d.p.i. indicating intact innate and adaptive immunity. Similarly, BCG burden declined remaining only in the spleen at 16-w.p.i. Despite effective bacterial clearance, following Lm infection WT/mut mice revealed liver lesions with hepatocyte necrosis, dense immune infiltrates, and collagen deposition. In both models, WT/mut mice failed to restore normal splenic architecture. Flow cytometry, F4/80 staining, and macrophage gene expression confirmed that macrophage numbers were not reduced, suggesting that CSF1R deficiency alters macrophage phenotypes rather than abundance.
These findings indicate that CSF1R signalling is dispensable for antimicrobial defence but critical for macrophage-mediated resolution of inflammation. Ongoing work aims to define how impaired CSF1R signalling limits macrophage plasticity and tissue repair.