Enhanced Proliferation of Ly6C+ Monocytes/Macrophages Contributes to Chronic Inflammation in Skin Wounds of Diabetic Mice
- 21 December 2020
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 206 (3), 621-630
- https://doi.org/10.4049/jimmunol.2000935
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.Keywords
Funding Information
- National Institute of General Medical Sciences (R01GM092850, R35GM136228)
- National Center for Advancing Translational Sciences (UL1TR002003)
This publication has 54 references indexed in Scilit:
- Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseasesBiomarker Research, 2014
- The C-type Lectin Receptor CLECSF8 (CLEC4D) Is Expressed by Myeloid Cells and Triggers Cellular Activation through Syk KinaseJournal of Biological Chemistry, 2012
- Tumor necrosis factor‐alpha (TNF‐α) is a therapeutic target for impaired cutaneous wound healingWound Repair and Regeneration, 2011
- Inflammation and wound healing: the role of the macrophageExpert Reviews in Molecular Medicine, 2011
- CCL2/MCP-1 modulation of microglial activation and proliferationJournal of Neuroinflammation, 2011
- IL-10 Controls Cystatin C Synthesis and Blood Concentration in Response to Inflammation through Regulation of IFN Regulatory Factor 8 ExpressionThe Journal of Immunology, 2011
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Impaired wound healing in mouse models of diabetes is mediated by TNF-α dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1)Diabetologia, 2009
- Localization of CORO1A in the Macrophages Containing Mycobacterium lepraeACTA HISTOCHEMICA ET CYTOCHEMICA, 2006
- Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators.Genes & Development, 1990