A Modified Collagen Gel Resolves Wound Inflammation Via Microrna-21-dependent Pro-healing Macrophage Polarization
AMITAVA DAS, Motaz Abas, Savita Khanna, Sashwati Roy, Chandan K. Sen.
Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Background- Collagen based dressings are widely used in wound care yet their mechanisms of action remain to be understood. Previous studies using a modified collagen gel (MCG) dressing demonstrated robust vascularization of ischemic wounds and improved healing outcomes. Wound macrophages play a critical role in enabling wound angiogenesis and timely healing. Thus, in this work, we sought to investigate the direct action of MCG dressing on wound macrophage phenotype and function. Methods- Wound cells were isolated from MCG treated PVA sponges implanted subcutaneously on the back of mice. Results- MCG increased macrophage recruitment to the wound site and promoted polarization to pro-healing (mϕheal) phenotype indicative of robust inflammation followed by timely resolution (p˂0.05; n=4). Increased mϕheal phenotype polarization was associated with copious production of anti-inflammatory cytokine IL-10 and proangiogenic VEGF suggesting a direct action of MCG on wound macrophages in supporting resolution of inflammation and improving angiogenesis (p˂0.05; n=4). Impaired clearance of apoptotic cell bioburden at wound-site feeds chronic inflammation. Previous studies in our laboratory reported that engulfment of apoptotic cells by macrophages (efferocytosis) drives polarization of pro-inflammatory macrophages (mϕinf) to mϕheal via a miR-21-PDCD4-IL-10 pathway. Significantly increased (p˂0.05; n=4) efferocytosis index was noted in macrophage from MCG treated wounds. Such favorable outcome resulted in a significant induction (p˂0.05; n=4) of miR-21 expression. Implicating miR-21 as a causative factor, MCG mediated induction of IL-10 in wound macrophages was blunted under conditions of miR-21 knockdown by miR-21-zip. Pharmacological inhibition of JNK in macrophages resulted in attenuated IL-10 production by MCG, indicating a role of miR-21-JNK pathway in MCG-mediated IL-10 release in macrophages. Conclusion- The findings of this work provide a novel paradigm in macrophage-ECM interactions as well as reshape the understanding of the mechanisms of action of collagen based dressings in the treatment of chronic wounds.
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