Parenteral re-exposure to an immunologically tolerated protein up to 6h after skin injuries improves wound healing in diabetic mice

Abstract

IntroductionOral tolerance is an immunological phenomenon defined by specific inhibition of immune responses to proteins contacted by the oral route. However, parenteral re-exposure to orally-tolerated proteins has systemic effects that reduce inflammation to unrelated agents injected soon afterward. Chronic skin wounds are major complications for diabetic patients, which may be related with pro-inflammatory conditions in the wound bed, as well as with impaired angiogenesis. We used a mouse-model of streptozotocin-induced diabetes to test whether injection of a regular dietary protein (zein) concomitantly with skin lesions reduces wound bed inflammation and improves wound healing in diabetic mice. MethodsC57BL/6 mice fed a standard chow containing zein (corn protein) were turned diabetic by streptozotocin injection. Two full skin thickness excisional wounds were created on the dorsum of anaesthetized mice. Experimental groups received one i.p. injection of 10 μg zein in adjuvant, 10 min before or 6 h after wounding and were sacrificed 7 and 40 days thereafter. Skin samples were processed and examined macroscopically and microscopically. ResultsIntraperitoneal injection of zein either before or after skin injuries, reduced the number of leukocytes (CD45+ cells) and of myofibroblasts, increased the number of alternatively activated (M2) macrophages, increased the expression transforming-growth factor (TGF)-β3 and rescued angiogenesis in the wound bed of diabetic mice. Zein treatment reduced the scar area and improved the organization of collagen fibers in the neodermis. ConclusionParenteral re-exposure to a protein previously contacted by the oral route concomitantly with or 6 h after skin injuries reduces wound inflammation and improves wound healing in diabetic mice.