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 but are gaining recognition for their critical role in inflammation. Here, we identify fibroblast-derived C-C motif chemokine ligand 2 (CCL2) as a key mediator of host defense against invasive Staphylococcus aureus infection. Single-cell RNA sequencing revealed that fibroblasts are a predominant source of CCL2 under steady-state conditions in both human and mouse skin. The use of mice with a conditional deletion of CCL2 in fibroblasts demonstrated that the expression of CCL2 by fibroblasts alters macrophage cytokine production and antigen-presentation-associated responses and is important for monocyte recruitment. Additionally, we revealed 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.