The extracellular matrix maintained by hypodermal macrophages via IGF1 is a niche for Staphylococcus aureus infection

Abstract Macrophages (MΦ) play a vital role in tissue homeostasis, but their functions in skin hypodermis, a common site of Staphylococcus aureus (S. aureus) infection, remains largely unexplored. Using flow-cytometry, bulk RNA-seq and single-cell RNA-seq, two MΦ subsets with distinct transcriptomes were uncovered. Both MΦ subsets relied on colony stimulating factor 1 (CSF1) receptor signaling for their survival. Single-cell RNA-seq of non-immune cells identified fibroblasts (FB) as a major source of dermal and hypodermal CSF1. Analysis of dermal and hypodermal stromal cells transcriptomes revealed Tek (encoding Tie2) in hypodermal FB as a potential driver for skin layer-specific ablation of CSF1. Tek-cre x Csf1-floxed mice (Csf1ΔTek) displayed a striking post-natal ablation of hypodermal MΦ associated with an alteration of the collagen network and increased accumulation of hyaluronic acid (HA). Generation of a ligand-receptor map identified candidate genes involved in hypodermal MΦ-FB crosstalk. Among which, depletion of insulin-like growth factor 1 (IGF1) from MΦ in Csf1r-cre x Igf1-floxed (Igf1ΔCsf1r) recapitulated the alteration of the ECM observed in absence of hypodermal MΦ. Interestingly, upon injecting S. aureus into the hypodermis, Csf1ΔTek and Igf1ΔCsf1r mice displayed striking reduction of the cellulitis phenotype as compared to WT mice. Pre-injection of HA attenuated cellulitis in WT mice, suggesting that deposition of HA in the absence of MΦ or MΦ-derived IGF1 conferred host protection against S. aureus. Thus, while hypodermal MΦ critically maintained ECM homeostasis, this provided a niche for S. aureus infection, highlighting implications for novel therapeutic strategies in S. aureus soft-tissue infections.