Apoptosis in autoimmune diabetes: the fate of beta-cells in the cleft between life and death

Abstract

Cytokine-induced beta-cell death is the end-stage event in the pathogenesis of autoimmune diabetes. Beside cytokines, several pro-apoptotic pathways mediated through nitric oxide, reactive oxygen species, glucose and Fas ligation can be involved, suggesting that programmed cell death (PCD) is a critical aspect in this process. The apoptotic program is activated by the utilization of the Fas/Fas-ligand (FasL) axis in the interrelation of T and beta-cells. Evidence for this mechanism arose from the finding that beta-cells in NOD mice could be protected from apoptosis by blocking the Fas-FasL pathway. Glucose is a regulator of Fas expression on human beta-cells and elevated glucose levels may contribute to accelerated beta-cell destruction by constitutively expressed FasL independently of the autoimmune reaction. It can thus be concluded that immunological, as well as metabolic, pathways may act in concert to cause beta-cell destruction. Much experimental work has been carried out to manipulate beta-cells in transgenic mice expressing apoptosis modulators in islets. For example, the transcription factor, nuclear factor-kappaB (NF-kappaB), promotes the expression of several beta-cell genes, including pro- and anti-apoptotic genes. The prevention of cytokine-induced gene expression of several NF-kappaB targets, such as inducible nitric oxide synthase, Fas, and manganese superoxide dismutase can prevent beta-cell death. Thus, modulating the expression of apoptotic mediators may significantly affect the end-stage outcome of autoimmune diabetes and could thus be a potential avenue for clinical therapy, even though currently existing findings remain exploratory due to the restrictions of transgenic mouse models.

Figure 1. Apoptotic pathways

A. Apoptosis signaling by CD95. DD: death domain. DED: death effector domain. CD95L (FasL) is a homotrimeric molecule. Each CD95L trimer binds three CD95 molecules. CD95 and CD95L play an important role in different types of physiologic apoptosis: 1. peripheral deletion of activated mature T cells; 2. killing of targets such as virus-infected cells or, in the case of T1DM, β-cells cells by cytotoxic T cells; 3. killing of inflammatory cells. The adapter protein FADD binds through its own death domain to the clustered receptor death domains. FADD contains a "death effector domain" that binds to an analogous domain repeated in tandem within the zymogen form of caspase 8 (also called FLICE). Upon recruitment by FADD, caspases 8 and 10 then activates downstream effector caspases committing the cell to apoptosis [4]. IL-1α and IFN-γ upregulate expression of Fas on islet cells [17]. B. Proapoptotic and antiapoptotic signaling by TNFR1. Unlike CD95L, TNF triggers apoptosis unless protein synthesis is blocked, which suggests the preexistence of cellular factors that can suppress the apoptotic stimulus generated by TNF. TNF trimerizes TNFR1 upon binding, inducing association of the receptors' death domains. Subsequently, an adapter termed TRADD binds through its own death domain to the clustered receptor death domains. C. Signaling by DR4 and DR5 and its modulation by decoy receptors. Overexpression of DR4 or DR5, which bind Apo2L, triggers apoptosis. There are divergent results regarding the required adaptor for the death domain of DR4 and DR5 [4]. Exposure to TNF-α and INF-γ leads to upregulation of TRAIL that binds to DR4 on β-cells and subsequently leads to a higher rate of β-cell apoptosis [27]. Figure modified according to [4].

Figure 2. Human diseases and animal models of death ligand/receptor signaling defects

ALPS Ib is the human genetic counterpart of the gld mice and corresponds to FasL blockade in mice. NOD mice heterozygous for the FasL mutation gld express low FasL levels on their T lymphocytes and exhibit delayed progression to diabetes. Fas-deficient NOD.lpr/lpr mice are resistant to T cell-mediated apoptosis. Transgenic animals expressing an inhibitor of caspase 8 do not develop lymphoproliferation although all death-receptor pathways are blocked. Upregulation of cFLIP has the same effect and secures insulin secretion in the insulin-secreting cell line βTc-Tet. Transgenic expression of CrmA in RIP-NOD mice inhibits caspases 8 and 10 and leads to delayed diabetes onset induced by diabetogenic spleen cells. Figure modified according to [9].