Macrophages promote collagen deposition through circadian regulation of fibroblasts.

Fibroblast collagen deposition is regulated by macrophages and the circadian rhythm; understanding how these processes interact provides insights to collagenous tissue homeostasis. Here, we reveal that macrophage-fibroblast interaction enhances collagen deposition and requires a functional circadian rhythm. Macrophage polarization status determines how fibroblast responses were elicited, where naive and pro-inflammatory macrophages require direct cell-cell contact, and anti-inflammatory macrophages secrete soluble factors. One key secreted factor identified by mass spectrometry proteomics analysis is PDGFA. Crucially, macrophages lacking PDGFA, or treatment with PDGFRa inhibitor, showed diminished ability to modulate fibroblast circadian rhythms and collagen production. Impaired circadian rhythms in either cell type also led to a reduced collagen fibrillogenesis response. These results confirmed that the collagen deposition pathway is under circadian clock control in lung fibroblasts, and demonstrated that macrophages can re-synchronize fibroblast circadian rhythms to promote collagen deposition and extracellular remodeling, which are implicated in processes such as wound healing responses.