Poor wound healing in diabetes is associated with increased chronic inflammation and alterations in macrophage accumulation. Chronic inflammation can alter the phenotype of macrophage precursors, monocytes but whether their phenotype is changed in association with wound healing is not known. Blood was obtained from 21 patients (14 male: 7 female) attending the High Risk Foot Clinic at RPA Hospital at their initial visit (V1), week 4 (V2) and week 8 (V3). Wound area was measured and wound type was assessed by a podiatrist. Monocyte number (CD14+), phenotype as classical (CD16−), non-classical (CD16++), and intermediate (CD16+), anti-inflammatory (CD163+) subset and expression of receptors CCR2, CCR5 and TLR2, TLR4 were determined by flow cytometry. The MMPs and TIMP-1 were measured in plasma by zymography and ELISA. Over the 8 weeks, 6 ulcers healed (H) and 15 failed to heal (NH). The age, duration of diabetes, HbA1c, wound size and duration at V1 were not different between the groups but the % CD16++ monocytes was higher in H vs. NH at V1 (23.5 vs. 8.3) and V3 (17.4 vs. 7.2) and monocyte CCR2+ was lower in H at V3 (P<0.05). Interestingly plasma MMP-3 and MMP-9/TIMP-1 ratio were higher in H at V1 but MMP-9 was lower in H at V3 (P<0.05). The wound area at V1 was not associated with wound closure rate (WCR: r=0.39, P=0.08). However for all samples at V2+V3, the WCR correlated with monocyte %CD16++ (r=0.42), CD16+ (r=0.39), CD163+ (r=0.37), and CD14+ (r=-0.39), CD16- (r=-0.52), as well as plasma MMP-2 (r=-0.67) and MMP-9 (r=-0.41)(P<0.05). At either V2 or V3, the relationship was maintained for monocyte %CD16++and CD16- and plasma MMP-2 (P<0.05). These results in people with diabetic foot ulcers suggest that circulating monocyte phenotype is altered as the wound heals. The positive relationship in WCR with monocyte anti-inflammatory profile suggests a predictive role for these markers. Whether the transition of monocytes from a pro- to an anti-inflammatory phenotype plays a mechanistic role in wound healing remains to be elucidated.
D. Min: None. V.L. Nube: None. A. Tao: None. X. Yuan: None. B. Brooks: None. J. Wong: Speaker's Bureau; Self; Novo Nordisk A/S, AstraZeneca, Eli Lilly and Company. S.M. Twigg: Advisory Panel; Self; Abbott. Consultant; Self; Abbott. Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Other Relationship; Self; Abbott. S. McLennan: None.