Macrophage-fibroblast mutual crosstalk in skin adventitia maintains hypodermal integrity

Authors

• B Voisin
• T Doebel
• Y Hu
• M Kelly
• T Kobayashi
• D Kim
• S Sohn
• S Abboud-Werner
• M Kelley
• C Yan
• K Nagao

Abstract

The skin is a multilayered and highly immunologically active organ. Skin macrophages (Macs) have been described as important orchestrators of wound healing processes by regulating endothelial cell and fibroblasts biology. However, little is known about their contribution to skin homeostatic functions during steady-state. Particularly, the biology of Macs of the deepest layer of the skin, the hypodermis, remains largely unexplored. Using flow cytometry, bone-marrow transfer, and a parabiotic mouse model, we found that dermal and hypodermal Macs were comprised of tissue-resident (TR-Macs) and monocyte-derived (Mono-Macs) macrophages. Analysis of Ccr2-/- and Csf1-op transgenic mice revealed that Mono-Macs in dermis and hypodermis were bone marrow dependent and that both dermal macrophage subsets were highly sensitive to changes in stroma-derived CSF1. To further explore Mac function(s), we performed single-cell RNA sequencing on wild-type, Ccr2-/- and Csf1-op/wt dermal and hypodermal cells. Alteration of Macs populations in Ccr2-/- and Csf1-op/wt mice were associated with considerable transcriptomic changes within hypodermal fibroblasts. Particularly, expression of transcripts associated with the extracellular matrix were preferentially altered. Using our single cell data, we identified the fibroblasts and endothelial cells, both of which expressed Tek, as the major source of CSF1, and generated a mouse model (Tek-cre x Csf1-Flox) to specifically deplete hypodermal Macs. Strikingly, staining skin sections uncovered that the absence of adventitia Macs was associated with a decrease of fibrillary collagen into the hypodermis resulting in a hyperelastic skin phenotype. Thus, our work provides evidences for a macrophage-fibroblasts cross-talk essential to the integrity of the hypodermis under steady-state conditions.

Scientific Focus Area: Immunology

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