Peritoneal macrophages regulate distal wound healing via endocrine release of plasma fibronectin
Lilian Salm, Simone N. Zwicky, Daniel Spari, Tural Yarahmadov, Marie Siwicki, Fernanda Vargas e Silva Castanheira, Jonas Zbinden, Deborah Stroka, Joel Zindel, Antoine Dufour, Paul Kubes, Guido Beldi
Lilian Salm, Simone N. Zwicky, Daniel Spari, Tural Yarahmadov, Marie Siwicki, Fernanda Vargas e Silva Castanheira, Jonas Zbinden, Deborah Stroka, Joel Zindel, Antoine Dufour, Paul Kubes, Guido Beldi
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Research Article Cell biology Immunology

Peritoneal macrophages regulate distal wound healing via endocrine release of plasma fibronectin

Abstract

The peritoneal cavity contains a large population of GATA6-expressing large peritoneal macrophages (LPMs), known to support healing of intraabdominal organs. In this study, we aimed to explore their full sphere of influence by examining their ability to perform wound healing at distant sites outside the cavity. In a mouse model combining a remote skin injury with peritoneal stimulation we observed a significant acceleration of skin wound healing in response to LPM activation. Tracking GATA6-expressing LPMs, we demonstrated that LPMs do not migrate to distant wound sites following peritoneal activation. Using parabiosis experiments and administration of activated peritoneal contents indicated an important role of molecules secreted by LPMs in remote skin wound healing. More specifically, proteomic and transcriptomic analyses identified fibronectin as a key factor produced by activated LPMs. In fact, depletion of LPMs or genetic knockout of fibronectin in myeloid cells eliminated the enhanced healing effect. These findings highlight the endocrine function of LPMs in systemic tissue repair, challenging the traditional perspective of plasma fibronectin being exclusively liver derived. Our results suggest that LPMs, strategically positioned in the peritoneal cavity, serve as a source of circulating fibronectin, promoting matrix formation and accelerating wound healing at distant sites.

Authors

Lilian Salm, Simone N. Zwicky, Daniel Spari, Tural Yarahmadov, Marie Siwicki, Fernanda Vargas e Silva Castanheira, Jonas Zbinden, Deborah Stroka, Joel Zindel, Antoine Dufour, Paul Kubes, Guido Beldi

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Figure 1

Peritoneal stimulus accelerates skin wound healing.

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Peritoneal stimulus accelerates skin wound healing. (A) Illustration of ...
(A) Illustration of mouse model with punch excision (diameter 4 mm) in the wound-only (SW) group. For peritoneal stimulus (PS), median laparotomy was performed at same time as punch excision (B) Representative photographs of wound closure at days 0, 1, 3, 5, and 7; scale bar: 500 μm (C) Quantification of percentage wound closure rate (mean ± SEM) at days 1, 2, 3, 5, and 7 after injury using digital calipers. Percent wound closure calculated [(Ai-Af)/Ai], Ai represents initial wound area and Af represents final wound area. n = 12 (SW), n = 13 (PS + SW) for each timepoint (N = 3). (D) Representative H&E slides (E) and measurement of epithelial gap, day 1; black arrow, wound margin; scale bar: 200μm. n = 5 (both groups), N = 2, P ≤ 0.0001 (D and E). (F) Quantification of epidermal thickness, day 1, n = 4 (SW), n = 6 (PS + SW), N = 2, P = 0.0008. (G) Quantification length of epithelial tongue, day 1, n = 4 (SW), n = 6 (PS + SW), N = 2, P = 0.0252. (H) Quantification of percentage wound closure at dorsum, day 1, n = 5 each group, N = 2, P = 0.0231. (I) Quantification of percentage wound closure, day 1. SW (n = 11), PS + SW (n = 6), extraperitoneal injury (n = 6), LPS (n = 5), ATP (n = 4), heat-inactivated E. coli (n = 5), E. coli 103 (n = 4), E. coli 105(n = 4), E. coli 109(n = 4), N = 2, SW + PBS / PS + SW + PBS: P = 0.0007, SW + PBS / LPS: P < 0.0001, SW + PBS / ATP: P = 0.0156, SW + PBS / heat-inact. E. coli: P = 0.0007, SW + PBS / E. coli 103: P = 0.0105, SW + PBS / E. coli 105: P = 0.0005, F = 9.846 (K) Representative IMC images of skin wound 24 hours, SW or PS + SW, SW (n = 3), PS + SW (n = 3), N = 1 (J) t-SNE plot showing 14 distinct cell types in the skin wounds, 24 hours postoperative (L) Representative IMC images, DNA (blue), collagen (red) in skin wounds (M) Quantification of collagen (MFI), P = 0.0343 unpaired t test. Unless otherwise indicated, images and data denote single mice from one representative experiment; independent experiments yielded similar results (representative of N ≥ 2 [N = 1 IMC]). K and L are generated from same IMC tissue section.*P < 0.05, **P < 0.01, ***P < 0.001; Student’s t test (C, D, E, F, G, H, M); 1-way ANOVA with Tukey`s post hoc test (I) A and mouse scheme of H was created using BioRender.