Journal article
Ly6C(Hi) Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus
Arteriosclerosis, thrombosis, and vascular biology, Vol.38(5), pp.1102-1114
05/01/2018
DOI: 10.1161/ATVBAHA.118.310703
PMCID: PMC5920725
PMID: 29496661
Abstract
Objective Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown.
Approach and Results Here, we characterized the kinetics and function of Ly6C(Hi) [Lin(-) (CD3(-)CD19(-)NK1.1(-)Ter-119(-)) Ly6G(-)CD11b(+)] and Ly6C(Lo) [Lin(-) (CD3(-)CD19(-)NK1.1(-)Ter-119(-)) Ly6G(-)CD11b(+)] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato-labeled Ly6C(Hi) monocyte/macrophages, we show Ly6C(Hi) cells transition to a Ly6C(Lo) phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C(Hi) cells that fail transition to Ly6C(Lo). The second wave of Ly6C(Hi) cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C(Hi) influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C(Hi) [Lin(-)Ly6G(-)CD11b(+)] and Ly6C(Lo) [Lin(-)Ly6G(-)CD11b(+)] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C(Hi) cells demonstrated differences in proinflammatory and profibrotic genes compared with controls.
Conclusions Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b(+)Ly6C(Hi) monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.
Details
- Title: Subtitle
- Ly6C(Hi) Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus
- Creators
- Andrew Kimball - Franklin & Marshall CollegeMatthew Schaller - Department of Pathology (M.S., S.L.K.).Amrita Joshi - Franklin & Marshall CollegeFrank M. Davis - Franklin & Marshall CollegeAaron denDekker - Franklin & Marshall CollegeAnna Boniakowski - Franklin & Marshall CollegeJennifer Bermick - Department of Pediatrics (J.B.).Andrea Obi - Franklin & Marshall CollegeBethany Moore - University of Michigan–Ann ArborPeter K. Henke - Franklin & Marshall CollegeSteve L. Kunkel - Department of Pathology (M.S., S.L.K.).Katherine A. Gallagher - Franklin & Marshall College
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.38(5), pp.1102-1114
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/ATVBAHA.118.310703
- PMID
- 29496661
- PMCID
- PMC5920725
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Number of pages
- 13
- Grant note
- K08DK102357 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) DK-102357; NIH-T32 HL076123 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Wolfe Foundation R01HL137919 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01AI117229 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984354054302771
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