Cytokine conversations: Fibroblasts shape macrophage identity to enhance collagen clearance

Tissue remodeling critically depends on fibroblasts and macrophages, but the timely and coordinated induction of phenotypes that promote remodeling-associated extracellular matrix (ECM) and interstitial collagen degradation is poorly understood. Here, we exploit the potency of activated dermal fibroblasts and macrophage plasticity to study cell-cell interplay. We identify fibroblasts as vigorous stimulators of co-cultured macrophages' differentiation towards a collagen-clearing phenotype. Fibroblasts secrete several soluble factors with macrophage recruitment and stimulation potential, including M-CSF, CXCL-1, CCL2, IL-6, and TIMP-1. IL-6-driven upregulation of Mannose Receptor (MR, CD206), an endocytic collagen-clearance receptor, is identified as a key macrophage effector-response. Mouse dermal in situ collagen turnover models demonstrate that macrophage MR-dependent collagen-uptake constitutes a recruitable pathway that can readily facilitate collagen degradation and links IL-6 macrophage-stimulation to the process. Importantly, a novel fibroblast depleter system reveals that fibroblasts dictate macrophage differentiation and collagen-clearance in vivo. Our study establishes activated fibroblasts as critical orchestrators of macrophage functions with potential impact on physiological tissue remodeling and fibrosis.