A Modified Collagen Dressing Induces Transition Of Inflammatory To Reparative Phenotype Of Wound Macrophages
AMITAVA Das1, Motaz Abas2, Nirupam Biswas1, Pradipta Banerjee1, Nandini Ghosh2, Savita Khanna1, Edward Stout3, Sashwati Roy1, Chandan K. Sen1.
1Indiana University School of Medicine, Indianapolis, IN, USA, 2The Ohio State University, Columbus, OH, USA, 3Southwest technologies Inc, Kansas City, MO, USA.
Background: Collagen based dressings are widely used in wound care. However understanding of their mechanism of action is scanty. 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. Methods: In this work, we sought to investigate the direct action of MCG dressing on wound macrophage phenotype and function using a established murine PVA sponge model. Results: MCG increased macrophage recruitment to the wound site and attenuated pro-inflammatory (mϕinf) macrophage polarization (p˂0.05; n=3). Decreased mϕinf polarization was associated with increased production of anti-inflammatory cytokine IL-10 and proangiogenic VEGF (p˂0.05; n=6) indicative of a direct action of MCG in supporting resolution of inflammation and improving angiogenesis in wounds. Impaired clearance of apoptotic cell bioburden at wound-site enables chronic inflammation. Previous studies in our laboratory reported that engulfment of apoptotic cells by macrophages (efferocytosis) drives polarization of macrophages to reparative phenotype via a miR-21-PDCD4-IL-10 pathway. Elevated efferocytosis index (p˂0.05; n=4) was noted in macrophages from MCG treated wounds. Such favorable outcome resulted in a significant induction (p˂0.05; n=4) of miR-21 expression. Interestingly, MCG-mediated induction of IL-10 was blunted under conditions of miR-21 knockdown (p˂0.05; n=4) by miR-21-zip pointing towards miR-21 as a causative factor. Pharmacological inhibition of JNK in macrophages resulted in attenuated IL-10 (p˂0.05; n=4) production by MCG, implicating miR-21-JNK pathway in MCG-mediated IL-10 release by wound macrophages. Conclusion: This work presents direct evidence demonstrating that a collagen based wound care dressing may influence wound macrophage function and therefore modify wound inflammation outcomes.
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