Toll-Like Receptor 3 Is Critical to the Pancreatic Islet Milieu That Is Required for Coxsackievirus B4-Induced Type 1 Diabetes in Female Nonobese Diabetic Mice

Objective: Genetic and environmental influences play a role as triggers of type 1 diabetes mellitus (T1DM). Female nonobese diabetic (NOD) mice are useful for studying T1DM as they spontaneously develop T1DM, which can be accelerated by some viruses. Toll-like receptor 3 (TLR3) is believed to play a critical role in viral-induced T1DM and beta-cell destruction, because female Tlr3 knockout (Tlr3(-/-)) NOD mice are protected from Coxsackievirus B4 (CVB4)-induced acceleration of T1DM. However, the exact role(s) TLR3 plays in the pathogenesis of CVB4-induced T1DM remain unknown. Methods: This longitudinal study used immunostaining, laser capture microdissection, and reverse transcription real-time polymerase chain reaction of islets from female uninfected and CVB4-infected Tlr3(+/+) and Tlr3(-/-) NOD mice. Results: Islets isolated from female Tlr3(+/+) NOD mice 4 to 8 weeks of age had higher amounts of insulitis, Cxcl10, Il1b, Tnfa, and Tgfb1 expression compared with Tlr3(-/-) NOD mice. After CVB4 infection, Tlr3(+/+) NOD mice had higher amounts of insulitis and T-cell infiltration at 3 days after infection compared with Tlr3(-/-) CVB4-infected NOD mice. Conclusions: Toll-like receptor 3 is necessary for establishment of a pancreatic islet inflammatory microenvironment by increasing insulitis and cytokine expression that facilitates CVB4-induced T1DM in female NOD mice.