Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Abstract

Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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

“…Diabetic wounds are characterized by prolonged chronic inflammation and M⌽ inflammatory activities after acute inflammation, and by altered generation of cytokines and lipid mediators (38,50), which contributes to the impairment of pro-healing functions carried out by macrophages (M⌽s) (53,70). These features contribute to the lack of healing (38,52,70) and repair of injured peripheral nerves. The latter results in peripheral neuropathy and insensitivity to injury, and ultimately the poor healing of diabetic wounds such as foot ulcers (18).…”

“…NPD1 promotes resolution of inflammation by regulating leukocyte infiltration, increasing M⌽ phagocytosis and evacuation from inflammation site to lymphatic system after efferocytosis (60). NPD1, resolvin D1 (29,32,68), and 14,21-diHDHAs (33,47,69,70) accelerate wound healing. In addition, NPD1 also increases corneal nerve area and neural cell survival (5,6,11,16).…”

“…M⌽s also produce growth factors, including hepatocyte growth factor (HGF) (7, 73, 80 -82), pro-resolving, anti-inflammatory lipid mediators (20,39,57,70), and IL-10 (3,24,27,43). M⌽s or monocytes from blood or injury sites convert docosahexaenoic acid (DHA) to pro-resolving lipid mediators such as neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) (34,49,63,64), maresins (65), and resolvins (64), as well as 14,21-dihydroxyDHAs (47).…”

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…ROS generation in macrophages was assessed by using the probe 2,7-dichlorofluorescein diacetate (DCFH-DA, 10 mM; Sigma). After I/R (without H 2 O 2 ) treatment, macrophages were cultured with DCFH-DA in RPMI-1640 for 30 min, and DCFH-DA fluorescence was measured by using an excitation wavelength of 480 nm and an emission wavelength of 535 nm [50]. HGF and IGF-1 in MSC conditioned media (DMEM, under hypoxia condition) were analyzed by ELISA kits obtained from RayBiotech and R&D Systems, respectively.…”

Macrophages Recruitment and Activation by α-gal Nanoparticles Accelerate Regeneration and Can Improve Biomaterials Efficacy in Tissue Engineering

“…(5). In order for these macrophages to induce regeneration of the implant, they have to differentiate into a pro-healing state [52,53]. This can be achieved by activation of these macrophages which bind anti-Gal coated !-gal nanoparticles via the Fc/Fc#R interaction (Fig.…”