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Enhanced Proliferation of Ly6C+ Monocytes/Macrophages Contributes to Chronic Inflammation in Skin Wounds of Diabetic Mice

Jingbo Pang, Mark Maienschein-Cline and Timothy J. Koh
J Immunol February 1, 2021, 206 (3) 621-630; DOI: https://doi.org/10.4049/jimmunol.2000935
Jingbo Pang
*Center for Wound Healing and Tissue Regeneration, Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612; and
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Mark Maienschein-Cline
†Research Informatics Core, University of Illinois at Chicago, Chicago, IL 60612
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Timothy J. Koh
*Center for Wound Healing and Tissue Regeneration, Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612; and
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Key Points

  • Mo/MΦ proliferate at higher rates in wounds of diabetic compared with nondiabetic mice.

  • CCL2/CCR2 signaling promotes wound Mo/MΦ proliferation in mice.

Abstract

Diabetic wounds are characterized by persistent accumulation of proinflammatory monocytes (Mo)/macrophages (MΦ) and impaired healing. However, the mechanisms underlying the persistent accumulation of Mo/MΦ remain poorly understood. In this study, we report that Ly6C+F4/80lo/− Mo/MΦ proliferate at higher rates in wounds of diabetic mice compared with nondiabetic mice, leading to greater accumulation of these cells. Unbiased single cell RNA sequencing analysis of combined nondiabetic and diabetic wound Mo/MΦ revealed a cluster, populated primarily by cells from diabetic wounds, for which genes associated with the cell cycle were enriched. In a screen of potential regulators, CCL2 levels were increased in wounds of diabetic mice, and subsequent experiments showed that local CCL2 treatment increased Ly6C+F4/80lo/− Mo/MΦ proliferation. Importantly, adoptive transfer of mixtures of CCR2−/− and CCR2+/+ Ly6Chi Mo indicated that CCL2/CCR2 signaling is required for their proliferation in the wound environment. Together, these data demonstrate a novel role for the CCL2/CCR2 signaling pathway in promoting skin Mo/MΦ proliferation, contributing to persistent accumulation of Mo/MΦ and impaired healing in diabetic mice.

Footnotes

  • This work was supported by National Institute of General Medical Sciences Grants R01GM092850 and R35GM136228 to T.J.K. M.M.-C. was supported in part by National Center for Advancing Translational Sciences Grant UL1TR002003.

  • The sequences presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE154400.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BV
    Brilliant Violet
    DPBS
    Dulbecco’s PBS
    MΦ
    macrophage
    Mo
    monocyte
    scRNAseq
    single cell RNA sequencing.

  • Received August 10, 2020.
  • Accepted November 23, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Enhanced Proliferation of Ly6C+ Monocytes/Macrophages Contributes to Chronic Inflammation in Skin Wounds of Diabetic Mice
Jingbo Pang, Mark Maienschein-Cline, Timothy J. Koh
The Journal of Immunology February 1, 2021, 206 (3) 621-630; DOI: 10.4049/jimmunol.2000935

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Enhanced Proliferation of Ly6C+ Monocytes/Macrophages Contributes to Chronic Inflammation in Skin Wounds of Diabetic Mice
Jingbo Pang, Mark Maienschein-Cline, Timothy J. Koh
The Journal of Immunology February 1, 2021, 206 (3) 621-630; DOI: 10.4049/jimmunol.2000935
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Print ISSN 0022-1767        Online ISSN 1550-6606