Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.

Keywords: T cells; TRAIL; apoptosis; autoimmunity; immunoregulation; type 1 diabetes.

Figure 1

TRAIL-induced pro-apoptotic signaling pathway. The binding of TRAIL to TRAIL receptor 1 (TRAIL-R1) and/or TRAIL-R2 recruits FADD and caspase-8, forming the DISC. The FLICE-like inhibitory protein (FLIP) can compete with caspase-8 for FADD binding. The activation of caspase-8 is enhanced through cullin 3 ubiquitylation and, in type I cells, can activate caspase-3, leading to apoptosis. In type II cells, the processing of effector caspases is inhibited by the X-linked inhibitor of apoptosis protein (XIAP), necessitating additional signaling for apoptosis to occur. Caspase-8 cleaves the BH3-interacting domain death agonist (BID), which translocates to the mitochondria, activating BCL-2 antagonist killer 1 (BAK) and BCL-2-associated X protein (BAX). This causes mitochondrial outer membrane permeabilization (MOMP), leading to the release of SMAC (mitochondria-derived activator of caspase) and cytochrome C. SMAC can block XIAP’s inhibitory effect, while cytochrome C, together with apoptotic protease activating factor 1 (APAF-1), mediates the assembly of the apoptosome, which activates caspase-9 and amplifies caspase-3 activity.

Figure 2

Non-canonical TRAIL signaling pathway. Upon binding of TRAIL to its receptors, a secondary cytosolic complex is formed, consisting of FADD and caspase-8, which interact with RIPK1, tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) essential modifier (NEMO). TRAF2 recruits cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2) and the linear ubiquitin chain assembly complex (LUBAC), which attaches linear polyubiquitin chains to RIPK1. These complexes activate NF-κB, p38 MAPK, JNK, and ERK pathways. LUBAC is present in both complexes and aids in recruiting the IKK complex, leading to NF-κB activation. RIPK1 also triggers the activation of tyrosine-protein kinase SRC and STAT3, promoting cell invasion and migration. For a description of necroptosis, see the text.

Figure 3

Schematic representation of islet inflammation in T1D. Self-antigens released by damaged β-cells recruit antigen-presenting dendritic cells, which take up the immune complexes, migrate to the pancreatic draining lymph nodes, and activate pathogenic islet antigen-specific T cells. The activated diabetogenic T cells return to the pancreas, where CD8⁺ T cells induce apoptosis of the β-cells by secreting granzyme and perforin or through CD95L-mediated killing. Activated CD4⁺ T cells contribute to β-cell destruction by releasing proinflammatory cytokines. Treg cells can inhibit diabetogenic T cells and consequently prevent β-cell damage through the secretion of IL-10 and transforming growth factor (TGFβ); however, in T1D, Treg cells are defective [146].