Feline pancreatic islet-like clusters and insulin producing cells express functional Toll-like receptors (TLRs)

Abstract

Toll-like receptors (TLRs) are cellular receptors that recognize molecules derived from pathogens, endogenous molecules generated after cellular stress, and free fatty acids. TLR activation leads to a proinflammatory reaction that is fundamental in the initiation of an innate immune response and subsequent adaptive responses but also can damage tissues. TLRs are not only expressed within the immune system, but also in most other organ systems including the pancreas. TLR4 is expressed in pancreatic β-cells of rodents and humans and its stimulation affects insulin secretion in response to glucose. A low-grade inflammation is often associated with disturbed performance of β-cells and insulin resistance, the cardinal metabolic event of type-2 diabetes. Feline diabetes mellitus shares many similarities with type-2 diabetes in humans. Our objective was to elucidate the role of TLRs in feline pancreatic islets and islet-like clusters (ILC) that consist of islets with their adjacent tissue. We tested whether TLRs are triggered by their agonists and lead to the expression of inflammatory cytokines. We confirmed the expression of all known feline TLRs in pancreas and ILC. Furthermore, stimulation with TLR agonists increased IL-6 mRNA and protein content and the expression of other proinflammatory cytokines indicating a clear proinflammatory response. The reactivity to TLR ligands was stronger in β-cell enriched populations obtained after sorting by FACS indicating that inflammatory stimuli can also be generated within β-cells. We conclude that the microenvironment of feline β-cells harbor the potential for inflammatory reactions, that can be initiated by molecules released from bacteria or viruses or other molecules recognized by TLRs. Therefore infections associated with bacteriemia and viremia can induce inflammation in islets and damage the endocrine pancreatic tissue.