Role of Toll-Like Receptor Signaling in the Pathogenesis of Graft-versus-Host Diseases

Abstract

Graft-versus-host disease (GVHD) and infection are major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the leading causes of morbidity and mortality in HSCT patients. Recent work has demonstrated that the two complications are interdependent. GVHD occurs when allo-reactive donor T lymphocytes are activated by major histocompatibility antigens or minor histocompatibility antigens on host antigen-presenting cells (APCs), with the eventual attack of recipient tissues or organs. Activation of APCs is important for the priming of GVHD and is mediated by innate immune signaling pathways. Current evidence indicates that intestinal microbes and innate pattern-recognition receptors (PRRs) on host APCs, including both Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), are involved in the pathogenesis of GVHD. Patients undergoing chemotherapy and/or total body irradiation before allo-HSCT are susceptible to aggravated gastrointestinal epithelial cell damage and the subsequent translocation of bacterial components, followed by the release of endogenous dangerous molecules, termed pathogen-associated molecular patterns (PAMPs), which then activate the PRRs on host APCs to trigger local or systemic inflammatory responses that modulate T cell allo-reactivity against host tissues, which is equivalent to GVHD. In other words, infection can, to some extent, accelerate the progression of GVHD. Therefore, the intestinal flora's PAMPs can interact with TLRs to activate and mature APCs, subsequently activate donor T cells with the release of pro-inflammatory cytokines, and eventually, induce GVHD. In the present article, we summarize the current perspectives on the understanding of different TLR signaling pathways and their involvement in the occurrence of GVHD.

Keywords: GVHD; HSCT; PAMPs; TLRs.

Figure 1

Schematic graph of GVHD initiated by intestinal flora. Intestinal flora enter the systemic circulation through damaged intestinal mucosa, and then interact with Toll-like receptors (TLRs), leading to the upregulation of major histocompatibility complex class II (MHCII) and costimulatory molecules B7 on host APCs. The upregulation of MHCII and costimulatory molecules B7 present the first and second activation signals, respectively, to donor T cells for the production of cytokines (including IL-1, IL-6, IL-12, IL-21, IL-22, IL-23, TNF-α and IFN-γ). The cytokines then induce the differentiation of a sub-population of donor T cells (Th1/Th2). Subsequently, the activated donor-derived T cells attack target tissues or organs (including intestine, liver and skin) by direct cytotoxicity, and eventually leading to GVHD. PAMPs = pathogen-associated molecular patterns; APCs = antigen-presenting cells; Th1 = helper T cell 1; Th2 = helper T cell 2.

Figure 2

Diagram of LPS-induced TLR4 signaling. LPS, the breakdown bacterial component, binds to LBP, and then is released from the LPS-LBP complex, and is presented to CD14 and TLR4 on APCs, leading to the activation of TLR4. With the assistance of MD-2, an important component of activated TLR4, termed Toll/IL-1 receptor (TIR) homologous domain, binds to the C-terminus of cytoplasmic adaptor proteins MyD88, while the death domain (DD) at the N-terminus of MyD88 interacts with intercellular enzyme IL-1 receptor-associated kinase (IRAK), eventually resulting in the phosphorylation of IRAK and the activation of TNF-α receptor-associated factor 6 (TRAF-6). The phosphorylated IRAK binds to the activated TRAF, and the complex activates TGF-β-activated Kinase-1(TAK1), triggering the activation of inhibitor of κ polypeptide gene enhancer in B-cells (IκB) kinase, eventually activating the NF-κB signaling pathway. The NF-κB signaling pathway upregulates the expression levels of the target gene. The activated NF-κB signaling initiates the expression of target genes, leading to the damage of target organs. TLR4 = Toll-like Receptor-4; LBP = lipopolysaccharide-binding Protein; TIR = Toll-Interleukin-1-Receptor; TIRAP = Toll-Interleukin-1-Receptor Domain-containing Adapter Protein; MyD88 = Myeloid Differentiation Primary Response Protein-88; IRAK = Interleukin-1 Receptor-associated Kinase; IRAKM = Interleukin-1 Receptor-associated Kinase-M; TollIP = Toll-Interacting Protein; TRAF6 = Tumor Necrosis Factor Receptor-associated Factor-6; UbC13 = Ubiquitin-conjugating Enzyme-13; UEV1A = Ubiquitin-conjugating Enzyme E2-Variant-1; ECSIT = Evolutionarily Conserved Signaling Intermediate in Toll Pathways; TAK1 = TGF-β-activated Kinase-1; TAB1 = TAK1-binding Protein-1; TAB2 = TAK1-binding Protein-2; IKKs = Inhibitor of κ Light Polypeptide Gene Enhancer in B-Cells Kinase.