Dynamic Changes of Monocytes and Chemokine Pathway Signaling During Wound Healing Post-Burn Injury

Background:There are over 11 million people hospitalized for burns annually according to the World Health Organization, resulting in painful skin scar contractures and restricted movements, as well as mental and physical stresses. Up to 70% of deep dermal injury result in hypertrophic scars, which currently have no standard treatment or reliable outcome. Monocytes and cytokines play a significant role in wound healing, and when dysregulated can cause abnormal healing. This research investigated cytokine and chemokine pathway signaling at different stages after burn injury in patients with varying severities of injury. The aim of this research was an in-depth observational study to enhance our understanding of cytokines and their differential response in wound healing after post-burn injury, to help guide the search for targeted therapeutic treatments.Methods: Our research involving burn patients follows the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, and is approved by the Health Research Ethics Board at the University of Alberta. Burn patients treated in the Firefighter’s Burn Treatment Unit at the University of Alberta Hospital were recruited for this study. Healthy individuals were recruited as controls. Burn patients were stratified by burn total body surface area (TBSA) into minor (≤20% TBSA), moderate (21-50% TBSA), and severe (>50% TBSA). Peripheral blood samples were taken at 48 hours, 1 week, 1 month, and more where applicable post-burn in patients, and once in controls. Serum was isolated from blood to determine chemokines of stromal cell-derived factor 1 (SDF-1), monocyte chemoattractant protein-1 (MCP-1), and regulated upon activation normal T cell expressed and presumably secreted (RANTES), chemokines and other cytokines by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells were separated from the blood and stained for monocyte and chemokine receptors CXCR4, CCR2, and CCR5, and monocyte populations were quantified by flow cytometry. Statistical analysis was done by one-way ANOVA with a Tukey correction, and regression analysis was performed using Pearson’s Correlation analysis.Results: Burn injury increased the number of CD14+CD16+ expressing monocytes in burn patients compared to controls, with an earlier peak in severe burns. The monocytes expressing CD14+CD16- were significantly higher in mild burns at 4-7 days than that in controls (p<0.05). Burn injury increased CXCR4, CCR2, and CCR5 expression in CD14+CD16+ monocytes, with these cell populations responding differently to different cytokines, time, and burn severity. MCP-1 had a positive correlation 0-3 days after burn injury in severe burns (r2 = 0.7388). IL-6, IL-8, RANTES, and MCP-1 significantly increased with increasing burn severity (p<0.01). IL-10 and IL-1RA increased significantly at 0-3 days in severe burns compared to controls (p<0.0001), while BCA-1 increased significantly for 7-30 days in severe burns (p<0.0001).Conclusions: Circulating monocytes expressing CD14+CD16+ increased immediately after severe burn injury, and monocytes expressing CD14+CD16- increased early in minor burns. Burn injuries increased the chemokine receptor expression in the Mo expressing CD14+CD16+. Increasing cytokine levels of IL-6 with burn severity is also shown to promote a pro-fibrotic response, as well as IL-8 being beneficial but after passing a threshold in severe burns becomes detrimental. IL-10 and IL-1RA showing increases in the first 3 days post-burn injury, combined with previous research, suggest that antagonism immediately after burn injury may be therapeutic. The significant increases in BCA-1 in severe burns may suggest a novel impact of this cytokine in hyper-angiogenesis and further pathogeneses of fibrotic scarring post-burn injury. RANTES should be further explored in its aggregated or disaggregated forms as it has been suggested to have different effects, which could explain a later time point increase in mild burns representing tissue remodeling and an increase in severe burns early after injury as a pro-inflammatory role. The monocytes and the chemokine receptors expressed, serum cytokines, and other molecules involved in wound healing of burn patients and scar development need further study to find a therapeutic treatment and progress our understanding of the abnormal wound healing after burn injury.

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