Toll-like Receptor 2 Senses β-Cell Death and Contributes to the Initiation of Autoimmune Diabetes

Kim, Hun Sik; Han, Myoung Sook; Chung, Kiseon; Kim, Sunshin; Kim, Eun-Shil; Kim, Myoung Joo; Jang, Eunkyeong; Lee, Hyun Ah; Youn, Jeehee; Akira, Shizuo; Lee, Myung-Shik

doi:10.1016/j.immuni.2007.06.010

Cited by 186 publications

(177 citation statements)

References 46 publications

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“…Although TLR2 has been shown to be upregulated in NOD mice 30 and T1DM patients, 28 its role in contributing to the exacerbated inflammatory state of diabetic wounds is unclear. Furthermore, increasing experimental evidence indicates that engagement of the TLR2 by endogenous ligands may be a major trigger of inflammation in response to skin injury, ischemia, hemorrhagic shock, and ischemia/reperfusion injuries.…”

Section: Discussionmentioning

confidence: 99%

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Dasu

Thangappan

Bourgette

et al. 2010

Laboratory Investigation

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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 À/À 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, fullthickness 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 þ STZ and NOD mice (Po0.05) compared with nondiabetic C57BL/6J mice. MyD88 expression, interleukin receptor-associated kinase-1 phosphorylation, and nuclear factor-k B (NF-kB) activation were increased in diabetic wounds compared with nondiabetic wounds. Wounds of TLR2 À/À þ STZ mice showed less oxidative stress, decreased MyD88 signaling, NF-kB activation, and cytokine secretion. The wound closure was significant in TLR2 À/À þ STZ mice compared with C57BL/6J þ 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.

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Section: Discussionmentioning

confidence: 99%

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Dasu

Thangappan

Bourgette

et al. 2010

Laboratory Investigation

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“…Suppressive activity of Treg cells was determined as described with modifications. 73 After RBC lysis of SVF cells, CD4 C IL2RA C Treg cells were obtained using a MACS Regulatory T cell isolation kit (Miltenyl Biotech, 130-091-041) according to the manufacturer's recommendation. In brief, CD4 C T cells were purified by negativeselection method depleting non-CD4 C T cells.…”

Section: Treg Cells and Facsmentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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“…Insulitis severity was assessed as described [25] in normoglycaemic mice by an observer blinded to tissue source by counting at least 30 pancreatic islets per mouse from four parallel sections of different cut levels of the pancreas. Mice that became diabetic within 12 weeks of age were censored in each group (3/30 uninfected; 2/25 WT C. rodentium-infected; and 4/24 ΔespF C. rodentium-infected NOD mice) because of a paucity of islets available for counting.…”

Section: Fitc-dextran Assaymentioning

confidence: 99%

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

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Aims/hypothesis Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes. Methods Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [ΔespF]) of causing intestinal epithelial barrier disruption. Results Here we demonstrate that prediabetic (12-weekold) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting ΔespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8 + T cells, compared with uninfected NOD mice. Conclusions/interpretation This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8 + T cells and modulates insulitis.

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Toll-like Receptor 2 Senses β-Cell Death and Contributes to the Initiation of Autoimmune Diabetes

Cited by 186 publications

References 46 publications

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

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