Fibroblast-derived CCL2 orchestrates immune responses and defends against Staphylococcus aureus skin infection

Host defense against invasive bacterial infections of the skin is essential for survival. It involves a complex yet incompletely understood process of microbial recognition followed by innate and adaptive systems for communication between resident and recruited cells to mount an effective defense. Stromal fibroblasts have not been classically considered immunocytes, yet are gaining recognition for their critical roles in inflammation. Here, we identify fibroblast-derived C-C motif chemokine ligand 2 (CCL2) produced by stromal fibroblasts as a key mediator in host defense against invasive Staphylococcus aureus infection. Single-cell RNA sequencing revealed that fibroblasts predominantly express CCL2 under steady-state conditions in human and mouse tissues. Use of mice with a conditional deletion of CCL2 in fibroblasts demonstrates that the expression of CCL2 by fibroblasts alters macrophage cytokine production and antigen presentation and is important for monocyte recruitment. Additionally, we uncover a novel role for fibroblast-derived CCL2 in promoting fibroblast-to-adipocyte differentiation via ERK and P38 signaling, leading to reactive adipogenesis and enhanced production of the antimicrobial peptide cathelicidin. In mice with targeted deletion of CCL2 in fibroblasts, these host immune responses are impaired and S. aureus infection of the skin is greatly increased. These findings highlight fibroblast-derived CCL2 as a critical regulator of immunity and suggest its broader implications in inflammatory and infectious diseases.