Salicylate Prevents Virus-Induced Type 1 Diabetes in the BBDR Rat

Chaoxing Yang,Rita Bortell,Agata Jurczyk,Michael A Brehm,Dennis L Guberski,Elaine Norowski,Dale L Greiner,Christian W Grant,Philip Diiorio

doi:10.1371/journal.pone.0078050

Abstract

Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR) rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV) and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist) develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1β, IL-6, IFN-γ, IL-12, and haptoglobin (an acute phase protein) in KRV+pIC treated rats. Significant elevations of IL-1β and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1β, IL-6, IFN-γ and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus-induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes.

Highlights

Development of human type 1 diabetes requires a susceptible genetic background
Using proteomic analyses we previously reported that serum levels of haptoglobin increased dramatically in BioBreeding Diabetes Resistant (BBDR) rats treated with Kilham rat virus (KRV)+polycytidylic acid (pIC) [18]; here we confirm this finding by ELISA and further investigate the effect of salicylate to modulate haptoglobin levels
In this study we utilized the virus-inducible BBDR rat model to examine the effects of salicylate treatment to modulate type 1 diabetes progression

Summary

Introduction

Development of human type 1 diabetes requires a susceptible genetic background. most patients (~85%) have no family history of the disease and concordance is only ~50% among identical twins, indicating that expressivity of type 1 diabetes susceptibility genes is environmentally dependent [1,2]. Mechanistic studies of virus-induced diabetes are not feasible in humans, reliable virusinducible animal models are needed. When treated with the parvovirus Kilham rat virus (KRV) and a TLR3 agonist, polyinosinic:polycytidylic acid (pIC), BBDR rats develop diabetes at a high rate (~100%), with consistent kinetics (~2 weeks) [5,6]. This highly reproducible model allows us to dissect the progression of disease from viral infection to onset of hyperglycemia in distinct temporal stages. Microarray studies of pancreatic lymph nodes from KRVinfected BBDR rats show upregulation of many proinflammatory cytokine genes prior to diabetes onset [9]. Serum levels of proinflammatory cytokines and Creactive protein (CRP) are elevated in newly-diagnosed type 1 diabetes patients compared to age-matched controls [10], and increased TLR expression or responsiveness of PBMCs from these patients is associated with elevated NF-κB signaling [11,12]

Methods

Results

Conclusion