Abstract
ABSTRACTWound healing is a complex process that involves sequential phases that overlap in time and space and affect each other dynamically at the gene and protein levels. We previously showed that insulin accelerates wound healing by stimulating faster and regenerative healing. One of the processes that insulin stimulates is an increase in monocyte/macrophage chemotaxis. In this study, we performed experiments in vivo and in vitro to elucidate the signaling transduction pathways that are involved in insulin-induced monocyte/macrophage chemotaxis. We found that insulin stimulates THP-1 cell chemotaxis in a dose-dependent and insulin receptor-dependent manner. We also show that the kinases PI3K-Akt, SPAK/JNK, and p38 MAPK are key molecules in the insulin-induced signaling pathways that lead to chemoattraction of the THP-1 cell. Furthermore, both PI3K-Akt and SPAK/JNK signaling involve Rac1 activation, an important molecule in regulating cell motility. Indeed, topical application of Rac1 inhibitor at an early stage during the healing process caused delayed and impaired healing even in the presence of insulin. These results delineate cell and molecular mechanisms involved in insulin-induced chemotaxis of monocyte/macrophage, cells that are critical for proper healing.
Highlights
Wound healing involves a series of well-orchestrated cellular and molecular processes: hemostasis, inflammation, granulation tissue formation and angiogenesis, wound contraction and remodeling; which all occur in an orderly manner
Our previous work showed that insulin improves wound healing by stimulating monocyte/macrophage chemotaxis
We used a THP-1 cell, a monocyte/macrophage cell line, and a variety of approaches to elucidate the signaling pathways involved in insulininduced THP-1 cell chemotaxis
Summary
Wound healing involves a series of well-orchestrated cellular and molecular processes: hemostasis, inflammation, granulation tissue formation and angiogenesis, wound contraction and remodeling; which all occur in an orderly manner. At early stages of healing, inflammation plays an essential and integral role in initiating and regulating healing progression and determining how well a wound will heal. Monocyte/macrophages, mast cells, and lymphocytes all actively participate in the inflammatory response, monocyte/macrophages play a critical and strong regulatory role. Monocytes, when attracted to the wound site, are activated to differentiate into macrophages. Molecules that attract and activate monocyte/macrophages include: inflammatory. Received 10 April 2017; Accepted 28 September 2017 mediators, such as the chemokines monocyte chemoattractant protein one (MCP-1), macrophage inflammatory protein-1 (MIP)1α, the growth factor macrophage colony stimulating factor (M-CSF); pathogens such as bacteria and fungi; and fragments from extracellular matrix (ECM) molecules such as collagen and fibronectin (Barrientos et al, 2008; Diegelmann and Evans, 2004; Suh et al, 2005)
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