Apple Cortez Vollmers, Sunny Z. Wu, Anthony Altieri, Erika McCartney, Hannah Bender, Christopher D. Davidson, Wyne P. Lee, Juan Zhang, Crystal Hu, Surinder Jeet, Ben A. Hall, Ricardo A. Irizarry-Caro, Alberto Guarnieri, Endi K. Santosa, Jessica Preston, Salil Uttarwar, Jason A. Vander Heiden, Yein Chung, Willie Ortiz, Michael Long, Raymond Asuncion, Yeqing Angela Yang, Jean X. Jiang, Zora Modrušan, Subba R. Chintalacharuvu, Christine Moussion, Akshay T. Krishnamurty, Wenxian Fu, Sören Müller, Matthew B. Buechler, Shannon J. Turley
Fibroblast–macrophage crosstalk is well-established in vitro, and fibroblast-derived colony-stimulating factor 1 (CSF1) supports macrophages in select tissues. However, whether macrophages regulate fibroblasts in vivo remains unknown. Leveraging genetic mouse models, single-cell multi-omics, flow cytometry and imaging, we show that fibroblast depletion or loss of fibroblast-derived growth factors impacts skin macrophage populations in the dermis and hypodermis. Conditional deletion of Csf1 in Dpt+ fibroblasts progressively decreases CD64+ and CD11c+ macrophages, impairing skin wound healing. Reduced macrophage abundance disrupts fibroblast cell cycle regulation, metabolism and immune signaling, and increases fibroblast abundance, affirming a reciprocal relationship. In human systemic sclerosis (scleroderma), elevated fibroblast-derived CSF1 and increased macrophage abundance correlate with disease severity, implicating the CSF1–CSF1R axis in pathology. These findings provide in vivo evidence of macrophage regulation of fibroblasts, revealing a bidirectional interplay that advances understanding of tissue homeostasis and immune regulation in skin. Turley, Buechler and colleagues show that dermatopontin-expressing fibroblasts provide CSF1 to form a supportive niche for skin-resident macrophages. This interaction is important for skin tissue architecture and wound healing.