Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

Abstract

Dysfunction of macrophages (MΦs) in diabetic wounds impairs the healing. MΦs produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MΦs and the actions of NPD1 on diabetic MΦ functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MΦ depletion, MΦs isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MΦs in NPD1 biosynthesis, and NPD1 action on diabetic MΦ inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MΦs from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MΦs. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MΦs functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MΦs involved 1) attenuating MΦ inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MΦ production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MΦs-produced factor that accelerates diabetic wound healing and promotes MΦ pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MΦs for treatment of diabetic wounds.

PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection

“…Treatment with PEDF or DHA alone does not have a significant effect in corneal nerve regeneration (Cortina et al, 2010), demonstrating that the combination is necessary to synthetize NPD1 as well as possible other docosanoids. NPD1 is produced in tissues, such as the cornea, on demand after injury as a pro-resolving component to reduce inflammation (Hong et al, 2014; Schwab et al, 2007; Serhan et al, 2015). In a mouse model of influenza, NPD1 was shown to decrease viral replication, while in a human model of severe influenza, levels were inversely correlated with disease severity (Morita et al, 2013).…”

Macrophage-based therapeutic strategies in regenerative medicine

“…Intradermal injection of lipid mediators derived from docosahexaenoic acid (DHA) including resolvins and protectins have been shown to induce an M2-like macrophage phenotype, promote resolution of inflammation, and accelerate wound healing in diabetic mice [85, 86]. Another anti-inflammatory lipid mediator, lipoxin-A4 has been shown to reduce inflammation and promote corneal wound healing in mice [87] and has been suggested as a potential anti-inflammatory therapy for tendon inflammation [88].…”

Wound repair: role of immune–epithelial interactions

“…82 In addition, macrophages produce neuroprotectin/protectin D1, which has been implicated in accelerating diabetic wound healing. 83 Macrophages are also known to be a key source of NO, 84 which is mainly used for pathogen killing. However, NO also plays an important role in the early phase of wound healing by contributing to re-epithelialization, collagen deposition, and wound repair.…”