Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Abstract

fanxq@sh163. net.Patients with diabetes mellitus often develop corneal complications and delayed wound healing. How diabetes might alter acute inflammatory responses to tissue injury, leading to delayed wound healing, remains mostly elusive. Using a streptozotocin-induced type I diabetes mellitus mice and corneal epithelium-debridement wound model, we discovered that although wounding induced marked expression of IL-1b and the secreted form of IL-1 receptor antagonist (sIL-1Ra), diabetes suppressed the expressions of sIL-1Ra but not IL-1b in healing epithelia and both in whole cornea. In normoglycemic mice, IL-1b or sIL-1Ra blockade delayed wound healing and influenced each other's expression. In diabetic mice, in addition to delayed reepithelization, diabetes weakened phosphatidylinositol 3-kinaseeAkt signaling, caused cell apoptosis, diminished cell proliferation, suppressed neutrophil and natural killer cell infiltrations, and impaired sensory nerve reinnervation in healing mouse corneas. Local administration of recombinant IL-1Ra partially, but significantly, reversed these pathological changes in the diabetic corneas. CXCL10 was a downstream chemokine of IL-1beIL-1Ra, and exogenous CXCL10 alleviated delayed wound healing in the diabetic, but attenuated it in the normal corneas. In conclusion, the suppressed early innate/inflammatory responses instigated by the imbalance between IL-1b and IL-1Ra is an underlying cause for delayed wound healing in the diabetic corneas. Local application of IL-1Ra accelerates reepithelialization and may be used to treat chronic corneal and potential skin wounds of diabetic patients. (Am J Pathol 2016 http://dx

IL-24 Promotes Pseudomonas aeruginosa Keratitis in C57BL/6 Mouse Corneas

“…The heterodimer of S100A8 and A9, (also referred to as calprotectin), has been shown to prevent the growth of bacteria, fungi, and protozoa by chelating Mn +2 and Zn +2 ions (37–40). CXCL10, also known as interferon-γ-inducible protein 10 (IP-10), can act as a chemoattractant for natural killer cells and an important anti-microbial peptide (AMP) capable of directly killing PA and C. albicans (8, 41, 42). As shown in Fig.…”

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

“…siRNA targeting PEDF and control siRNA (20 μmol/L, 5 μl/eye, sc-40948, Santa Cruz Biotechnology.) were injected twice (24 h and 4 hours) before wounding, as described before49.…”

Diabetic complications in the cornea

“…Several treatments have also been recently reported to ameliorate some symptoms of diabetes in the cornea using animal models. These include 1,5-isoquinolinediol [poly(ADP-ribose) polymerase inhibitor] that increased corneal sensitivity and epithelial healing in diabetic rats (Byun et al, 2015); ciliary neurotrophic factor (downregulated in the diabetic cornea) that activated corneal epithelial stem cells, increased nerve density, and promoted epithelial healing through the activation of STAT3 in diabetic mice (Zhou et al, 2015); topical nerve growth factor that reduced apoptosis and inflammation in corneas of diabetic rats (Park et al, 2016); interleukin-1 receptor antagonist that increased epithelial wound healing, sensory reinnervation, and reduced apoptosis in diabetic mouse corneas (Yan et al, 2016); substance P that produced similar effects in diabetic mice and high glucose-treated corneal epithelial cells through neurokinin-1 receptor (Yang et al, 2014); curcumin that promoted wound healing and recovery of corneal sensation when used in nanomicelles with intranasal delivery; it may work through reduction of reactive oxygen species (Guo et al, 2016); and topically delivered mitogenic protein lacritin fused with elastin-like polypeptide–based nanoparticles that enhanced corneal epithelial wound healing in NOD diabetic mice (Wang et al, 2014). Although promising, most of these agents need to be studied in more detail including pharmacology and side effects.…”