Toll-Like Receptor Activation in Immunity vs. Tolerance in Autoimmune Diabetes

INTRODUCTION TOLL-LIKE RECEPTORS: KEY RECEPTORS OF THE INNATE IMMUNE SYSTEM The human body constantly encounters a diverse spectrum of pathogens. To defend itself, a complex immune system has evolved consisting of two subdivisions: the innate and the adaptive immune systems. The innate immune system constitutes the so-called “first line of defense” and acts through highly conserved germline-encoded pattern recognition receptors (PRRs) (1). These receptors bind to common pathogen-associated molecular patterns (PAMPs), which are vital for the survival of the microorganisms and cannot be altered by mutations. Pattern recognition receptors were first discovered in the fruit fly Drosophila melanogaster. The PRRs in Drosophila, named Toll, play an important role in the recognition of microorganisms such as fungi as well as coordinating embryonic development of the dorso-ventral axis. Homologs of Toll in vertebrates are called Toll-like receptors (TLRs). The first TLR in humans was described in 1997 (2). To date, another 9 TLRs have been identified in humans and 13 in mice. Among these, only murine TLR10 is nonfunctional due to retrovirus insertion (3). Except for TLRs 3, 7, 8, and 9, which are expressed intracellularly, TLRs are located on the surface of innate and adaptive immune cells as well as on non-immune cells such as muscle cells, epithelial cells, adipocytes, and pancreatic beta cells (1). Cell-surface TLRs detect exogenous lipids, lipoproteins, and proteins from microbes; intracellular TLRs recognize bacterial and viral nucleic acids (3). Recognition of their cognate ligand triggers a complex signaling cascade that ultimately results in the induction of various pro-inflammatory chemokines and cytokines and the activation of the adaptive immune system. However, the activation of TLRs and the subsequent induction of inflammatory immune responses are not always beneficial to the host. TLRs are involved in the pathogenesis of various autoimmune and non-infective inflammatory diseases such as systemic lupus erythematosus, multiple sclerosis, arteriosclerosis, inflammatory bowel disease, diabetes, allergy, and cancer (4, 5). Their activation can either attenuate or boost the course of disease by inducing tolerance or triggering autoreactivity, respectively. The role of the TLRs in the pathogenesis of autoimmune-mediated diabetes, also referred to as type 1 diabetes (T1D), has been extensively studied (Table 1). T1D is a T-cell-mediated metabolic disorder with progressive destruction of insulinproducing pancreatic β cells (6). During the course of disease development,diabetogenic T-cells, macrophages, and dendritic cells will infiltrate the pancreatic islets and cause islet inflammation and eventually β cell loss. This opinion letter focuses on the beneficial and detrimental aspects of TLR induction in the course of T1D development.