Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas.
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-1β and the secreted form of IL-1 receptor antagonist (sIL-1Ra), diabetes suppressed the expressions of sIL-1Ra but not IL-1β in healing epithelia and both in whole cornea. In normoglycemic mice, IL-1β 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-kinase-Akt 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-1β-IL-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-1β 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.
Department of Ophthalmology, Graduate Program, Shanghai Ninth Peoples' Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
Chenxi
C
Yan
Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
Nan
N
Gao
Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
Haijing
H
Sun
Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
Jia
J
Yin
Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
Patrick
P
Lee
Department of Dermatology, Henry Ford Immunology Program, Henry Ford Health System, Detroit, Michigan.
Li
L
Zhou
Department of Ophthalmology, Graduate Program, Shanghai Ninth Peoples' Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: fanxq@sh163.net.
Xianqun
X
Fan
Department of Ophthalmology, Kresge Eye Institute, and the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: fyu@med.wayne.edu.
Fu-Shin
FS
Yu
D000818:Animals; D015153:Blotting, Western; D003316:Corneal Diseases / Q000209:etiology / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D014945:Wound Healing / Q000502:physiology*
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta