Reciprocal regulation of fibroblast–macrophage equilibrium governs skin integrity
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<sup>+</sup> fibroblasts progressively decreases CD64<sup>+</sup> and CD11c<sup>+</sup> 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.
Authors
- Christine Moussion (ORCID: https://orcid.org/0000-0002-1641-4094)
- Shannon J. Turley (ORCID: https://orcid.org/0000-0002-0444-3031)
- Endi K. Santosa (ORCID: https://orcid.org/0000-0001-9483-8354)
- Surinder Jeet (ORCID: https://orcid.org/0000-0002-0442-8579)
- Jason A. Vander Heiden (ORCID: https://orcid.org/0000-0002-1474-310X)
- Erika McCartney
- Apple Cortez Vollmers (ORCID: https://orcid.org/0000-0003-2787-0797)
- Subba R. Chintalacharuvu
- Jean X. Jiang (ORCID: https://orcid.org/0000-0002-2185-5716)
- Ricardo A. Irizarry-Caro (ORCID: https://orcid.org/0000-0002-1300-6626)
- Akshay T. Krishnamurty (ORCID: https://orcid.org/0000-0001-5382-1417)
- Willie Ortiz
- Crystal Hu
- Sunny Z. Wu (ORCID: https://orcid.org/0000-0002-6153-0449)
- Yeqing Angela Yang (ORCID: https://orcid.org/0000-0002-9868-7431)
- Ben A. Hall
- Yein Chung
- Wenxian Fu
- Alberto Guarnieri
- Raymond Asuncion
- Christopher D. Davidson
- Sören Müller
- Matthew B. Buechler
- Salil Uttarwar
- Jessica Preston
- Anthony Altieri
- Hannah Bender
- Michael Long
- Juan Zhang
- Zora Modrusan
- Wyne P. Lee
Institutions
- University Health Network (CA)
- The University of Texas at San Antonio Health Science Center (US)
- University of Toronto (CA)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-02-27
- DOI
- https://doi.org/10.1038/s41590-026-02434-5
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.43