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<p>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 <i>Csf1</i> in <i>Dpt</i><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.</p>

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Reciprocal regulation of fibroblast–macrophage equilibrium governs skin integrity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月27日

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  • Apple Cortez Vollmers,
  • Sunny Z. Wu,
  • Anthony Altieri,
  • Erika E. McCartney,
  • Hannah Bender,
  • Christopher D. Davidson,
  • Wyne P. Lee,
  • Juan Zhang,
  • Crystal Hu,
  • Surinder Jeet,
  • Ben 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 Modrusan,
  • Subba Chintalacharuvu,
  • Christine Moussion,
  • Akshay T. Krishnamurty,
  • Wenxian Fu,
  • Sören Müller,
  • Matthew B. Buechler,
  • Shannon J. Turley

摘要

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.