PMID- 29496661
OWN - NLM
STAT- MEDLINE
DCOM- 20190708
LR  - 20190708
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 38
IP  - 5
DP  - 2018 May
TI  - Ly6C(Hi) Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound 
      Healing in Diabetes Mellitus.
PG  - 1102-1114
LID - 10.1161/ATVBAHA.118.310703 [doi]
AB  - 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.
CI  - (c) 2018 American Heart Association, Inc.
FAU - Kimball, Andrew
AU  - Kimball A
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Schaller, Matthew
AU  - Schaller M
AD  - Department of Pathology (M.S., S.L.K.).
FAU - Joshi, Amrita
AU  - Joshi A
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Davis, Frank M
AU  - Davis FM
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - denDekker, Aaron
AU  - denDekker A
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Boniakowski, Anna
AU  - Boniakowski A
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Bermick, Jennifer
AU  - Bermick J
AD  - Department of Pediatrics (J.B.).
FAU - Obi, Andrea
AU  - Obi A
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Moore, Bethany
AU  - Moore B
AD  - Department of Microbiology and Immunology (B.M.), University of Michigan, Ann 
      Arbor.
FAU - Henke, Peter K
AU  - Henke PK
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.).
FAU - Kunkel, Steve L
AU  - Kunkel SL
AD  - Department of Pathology (M.S., S.L.K.).
FAU - Gallagher, Katherine A
AU  - Gallagher KA
AD  - From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., 
      K.A.G.) kgallag@med.umich.edu.
LA  - eng
GR  - R01 HL137919/HL/NHLBI NIH HHS/United States
GR  - T32 HL076123/HL/NHLBI NIH HHS/United States
GR  - K08 DK102357/DK/NIDDK NIH HHS/United States
GR  - P30 DK020572/DK/NIDDK NIH HHS/United States
GR  - R01 AI117229/AI/NIAID NIH HHS/United States
GR  - R01 HL132988/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180301
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Antigens, Ly)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Ly-6C antigen, mouse)
SB  - IM
MH  - Animals
MH  - Antigens, Ly/*metabolism
MH  - Cell Plasticity
MH  - Chemokine CCL2/metabolism
MH  - Chronic Disease
MH  - Diabetes Mellitus, Type 2/*blood/genetics/pathology/physiopathology
MH  - Diabetic Angiopathies/*blood/genetics/pathology/physiopathology
MH  - Diet, High-Fat
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - Inflammation/*blood/genetics/pathology/physiopathology
MH  - Inflammation Mediators/metabolism
MH  - Kinetics
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Monocytes/*metabolism
MH  - Phenotype
MH  - Signal Transduction
MH  - Skin Ulcer/*blood/genetics/pathology
MH  - *Wound Healing
PMC - PMC5920725
MID - NIHMS944203
OTO - NOTNLM
OT  - diabetes mellitus
OT  - inflammation
OT  - macrophages
OT  - monocytes
OT  - wound healing
COIS- Conflict of Interest Statement: The authors have no conflict of interest to 
      declare.
EDAT- 2018/03/03 06:00
MHDA- 2019/07/10 06:00
PMCR- 2019/05/01
CRDT- 2018/03/03 06:00
PHST- 2017/09/06 00:00 [received]
PHST- 2018/02/16 00:00 [accepted]
PHST- 2018/03/03 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2018/03/03 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - ATVBAHA.118.310703 [pii]
AID - 10.1161/ATVBAHA.118.310703 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2018 May;38(5):1102-1114. doi: 
      10.1161/ATVBAHA.118.310703. Epub 2018 Mar 1.