TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice.
Toll-like receptor-2 (TLR2) is a pivotal pathogen recognition receptor that has a key role in inflammation, diabetes, and injury. Hyperglycemia, inflammation, and oxidative stress induce TLR2-myeloid differentiation factor-88 (MyD88) expression and signaling, and are major pathophysiological mechanisms in the impaired diabetic wound-healing process. The aim of the study was to examine the contribution of TLR2-MyD88 expression and signaling to the prolonged inflammation observed in diabetic wounds. Diabetes was induced in male C57BL/6J and TLR2(-/-) mice using streptozotocin (STZ) with matching nondiabetic mice as control. In addition, nonobese diabetic (NOD) mice were used to represent the spontaneous type 1 diabetes condition. After 2 weeks of persistent hyperglycemia in the mice, full-thickness excision wounds were made on the backs aseptically. Total RNA and protein were subjected to real-time PCR and western blot analyses. Wound sizes were measured using digital planimetry. TLR2 mRNA and protein expression increased significantly in wounds of C57BL/6J+STZ and NOD mice (P<0.05) compared with nondiabetic C57BL/6J mice. MyD88 expression, interleukin receptor-associated kinase-1 phosphorylation, and nuclear factor-κ B (NF-κB) activation were increased in diabetic wounds compared with nondiabetic wounds. Wounds of TLR2(-/-)+STZ mice showed less oxidative stress, decreased MyD88 signaling, NF-κB activation, and cytokine secretion. The wound closure was significant in TLR2(-/-)+ STZ mice compared with C57BL/6J+STZ mice. Collectively, our findings show that increased TLR2 mRNA and protein expression, signaling, and activation contribute to the prolonged inflammation in the diabetic wounds and that absence of TLR2 may result in decreased inflammation and improved wound healing.
Dasu
Mohan R
MR
Department of Pathology, University of California Davis, Sacramento, CA, USA.
Thangappan
Ravi K
RK
Bourgette
Alika
A
DiPietro
Luisa A
LA
Isseroff
Rivkah
R
Jialal
Ishwarlal
I
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013311:Streptozocin; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014945:Wound Healing
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D013311:Streptozocin