Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

Abstract

Aims/hypothesis The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8 + T cells. Methods We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8 + T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). Results TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. Conclusions/interpretation TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

“…Despite our hypothesis, we found that both vancomycin and neomycin accelerated diabetes in NOD mice when compared with NOD mice given water only (Figure 3a). Similar to our previous studies showing~30% of NOD mice are diabetic by 20 weeks (Lee et al, 2011), B70% of antibiotic treated NOD mice were diabetic by 20 weeks. In support of this accelerated diabetes, the antibiotic-treated mice had more serum insulin autoantibodies, and altered gut lymphoid-associated effector T cells including increased interferon-g+ CD4+ T cells and reduced interleukin-17+ CD4+ T cells (Figures 3b-d).…”

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…In this study, we explored the ability of different TLR ligand-activated DCs to modulate uveitogenic Th17 development and found that TLR7 ligation significantly promoted autoreactive Th17 responses by enhancing IL-17 and RORgt expression in EAU. Our results showing that TLR7 activation enhanced the clinical signs of EAU by promoting Ag-specific CD4 + T cell responses are in agreement with most recent findings in other experimental models of autoimmune diseases, such as autoimmune diabetes and multiple sclerosis (25,39,40).…”

“…CL097 is a potent TLR7 agonist in mice (25)(26)(27)(28). In the current study, we addressed the role of TLR7 engagement in EAU development and associated mechanisms using a well-established EAU model.…”

Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats

“…Lee et al 14 showed that TLR7 stimulation increased the levels of proinflammatory cytokines and type 1/2 IFNs and in the pancreatic lymph nodes of young prediabetic NOD mice. TLR7 stimulation of NOD bone marrow-derived dendritic cells increased activation and production of proinflammatory cytokines.…”

“…In addition, TLR7 was identified as a macrophage-specific target to selectively induce autophagy in macrophages from atherosclerotic plaques. TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in NOD mice 14 .…”