title: 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.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; shong@lsuhsc.edu.
authors.forename: Song
authors.initials: S
authors.lastname: Hong
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Haibin
authors.initials: H
authors.lastname: Tian
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Orthopedic Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: James Monroe
authors.initials: JM
authors.lastname: Laborde
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Filipe A
authors.initials: FA
authors.lastname: Muhale
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Bhagwat V
authors.initials: BV
authors.lastname: Alapure
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital; Department of Anaesthesia (Biochemistry and Molecular Pharmacology), Harvard Medical School; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D018384:Oxidative Stress; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D014947:Wounds and Injuries
chemical_list: C487679:protectin D1; D004281:Docosahexaenoic Acids
keywords: anti-inflammatory and pro-resolving mediators; diabetic wound healing; macrophage; pro-healing and neurotrophic function