OBJECTIVE— Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic β-cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced β-cell death.
RESEARCH DESIGN AND METHODS— Primary rat β-cells and islet cells from wild-type, toll-like receptor (TLR) 3, type I interferon receptor (IFNAR1), or interferon regulatory factor (IRF)-3 knockout mice were exposed to external dsRNA (external polyinosinic-polycytidylic acid [PICex]) or were transfected with dsRNA ([PICin]).
RESULTS— TLR3 signaling mediated PICex-induced nuclear factor-κB (NF-κB) and IRF-3 activation and β-cell apoptosis. PICin activated NF-κB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2α phosphorylation, and triggered a massive production of interferon (IFN)-β. This contributed to β-cell death, as islet cells from IFNAR1−/− or IRF-3−/− mice were protected against PICin-induced apoptosis.
CONCLUSIONS— PICex and PICin trigger β-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.
Programmed cell death occurs naturally, as a physiological process, during the embryonic development of multicellular organisms. In the retina, which belongs to the central nervous system, at least two phases of cell death have been reported to occur during development. An early phase takes place concomitant with the processes of neurogenesis, cell migration and cell differentiation. A later phase affecting mainly neurons occurs when connections are established and synapses are formed, resulting in selective elimination of inappropriate connections. This pattern of cell death in the developing retina is common among different vertebrates. However, the timing and magnitude of retinal cell death varies among species. In addition, a precise regulation of apoptosis during retinal development has been described. Factors such as neurotrophins, among many others, and electrical activity influence the survival of retinal cells during the course of development. In this paper, we present a summary of these different aspects of programmed cell death during retinal development, and examine how these differ among different species.
The expression of brain derived neurotrophic factor (BDNF) and its preferred receptor (TrkB) in rat retinal ganglion cells (RGCs) have been determined in the present study. To identify RGCs retrograde labelling was performed with fluorogold (FG). Subsequently, retinas were immunostained with antibodies to BDNF and TrkB. We found that all RGCs labelled with FG express both BDNF and its preferred receptor, TrkB. Moreover, displaced amacrine cells were also found to be immunolabelled by both antibodies. Thus BDNF/TrkB signalling in RGCs probably involves endogenous BDNF produced by the RGCs themselves.
These findings demonstrate that the expression of NTs and their receptors within adult porcine RGCs is maintained in vitro, under conditions of limited interaction with neighboring neurons and deprived of afferent inputs and target tissue. TrkA may be involved in regeneration of nerve terminals.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.