Abstract
TLR4 is a transmembrane receptor of the innate immune system that recognizes LPS from gram-negative bacteria. Its stimulation induces pro-inflammatory responses and modulates adaptive immunity. Our aim is to determine the role of TLR4 in the activation and proliferation of T lymphocytes in the onset of autoimmune diabetes, using the non-obese diabetic (NOD) mouse model. Antigen-specific activation and proliferation of diabetogenic T cells were assessed in vitro by Carboxyfluorescein succinimidyl ester (CFSE) dilution, in presence of vehicle or CLI-095, a cyclohexene derivative that inhibits TLR4 signaling. NOD mice were treated with vehicle or CLI-095 and sacrificed either before or after the onset of autoimmune diabetes. T lymphocyte activation and proliferation were evaluated in treated and control mice. Insulitis was analyzed by histology and diabetes incidence was determined in treated and control mice. Our results demonstrate that TLR4 blockade decreases CD4+ T lymphocyte activation and auto-antigen-specific proliferation both in vitro and in vivo, decreases the infiltrative insulitis and finally prevents the onset of spontaneous diabetes. Taken together, our data demonstrate that TLR4 signaling contributes to the development and maintenance of autoimmune diabetes. The immunomodulatory effect of CLI-095 could be part of a preventive strategy targeting patients at risk for type 1 diabetes.
Highlights
Type 1 diabetes (T1D) is a multifactorial, inflammatory and autoimmune disease
We have gathered sufficient evidence suggesting TLR4 is involved in the pathogenesis of diabetes in non-obese diabetic (NOD) mice and that its blockade prevents the activation, cellular division, proliferation and differentiation of T lymphocytes into Th1 and Th17 effector lymphocytes
By inhibiting the effect of inflammatory mediators such as CXCL10, TLR4 inhibitor could prevent the recruitment of innate cells and prevent differentiation of lymphocytes into diabetogenic effector cells[13]
Summary
Type 1 diabetes (T1D) is a multifactorial, inflammatory and autoimmune disease. The importance of genetic and immunological factors in T1D is highlighted by the activation of T lymphocytes by autoantigens. It has been suggested that alteration of gut immunity and exposition to certain pathogens might be important contributors to the pathogenesis of T1D. In this context, TLR4 could be a major player in diabetes pathogenesis, since it recognizes bacterial LPS and damage associated molecular patterns (DAMPs). It has been shown that insulitis and the autoimmune process leading to overt T1D involve TLR4-expressing cells of the innate and adaptive immune system, but contradictory results have been reported on the development of T1D in mouse models bearing the general knock-out of TLR43,4. NOD mice, share genetic and immunological similarities with human T1D9 They produce autoantibodies, develop insulitis and progress to spontaneous autoimmune diabetes. We assessed in vivo and in vitro, the impact of TLR4 blockade on the function of diabetogenic T lymphocytes, and evaluated its impact on insulitis and the development of diabetes
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