Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren's Syndrome

Abstract

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

Keywords: Toll-like receptor; innate immunity; pattern-recognition receptor; salivary gland epithelial cell; type I interferon.

Figure 1

Schematic overview of the activation of the Toll-like receptor signaling pathway. Toll-like receptors (TLRs) are the pattern-recognition receptors, which recognize different pathogen- or danger-associated molecular patterns. TLR1, TLR2, TLR4, TLR5, and TLR6, which are involved in the recognition of proteins and fats, are mainly localized on the cell surface, whereas TLR3, TLR7, TLR8, and TLR9, which are involved in the recognition of nucleic acids, are mainly localized within the cells in the endosomes and endoplasmic reticulum. The TLR recognition of their ligands leads to the production of inflammatory cytokines and type I interferon via downstream molecules. Abbreviations: AP-1: activator protein 1; IRF: interferon regulatory factor; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa B; TIRAP: toll/interleukin-1 receptor domain-containing adapter protein; TLR: Toll-like receptor; TRAM: TRIF-related adaptor molecule; TRIF: TIRAP inducing interferon β.

Figure 2

Activation of type I interferon production via endosomal Toll-like receptors and RNA sensor signaling pathway in Sjögren’s syndrome. Endosomal Toll-like receptors (TLRs), RNA sensor retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene-5 (MDA5) expressed in salivary gland epithelial and infiltrating cells such as plasmacytoid dendritic and B cells in Sjögren’s syndrome induce mainly the production of type I interferon (IFN) via downstream molecules. The balance between TLR7 and TLR9 responses is controlled by Unc93B1, a protein responsible for trafficking TLR7 and TLR9 from the endoplasmic reticulum to the endosome, where TLR7 and TLR9 recognize nucleic acids. Disruption of this control may activate TLR7 signaling and lead to the overproduction of inflammatory cytokines and type I IFN. TLR7 ligand stimulation also enhances the expression of RIG-I and MDA5, synergistically producing a type I IFN signature. The overproduction of type I IFN specifically induces polyclonal B-cell expansion and B-cell differentiation into autoantibody-producing plasma cells. In addition, type I IFN-induced signaling can induce B-cell activating factor (BAFF) production and promote the activation and survival of B cells. The salivary gland epithelial cells in Sjögren’s syndrome are one of the source cells that produce BAFF after the stimulation of type I IFN. Abbreviations: BAFF: B cell-activating factor; IRAK1: interleukin-1 receptor-associated kinase 1; IRF: interferon regulatory factor; MAVS: mitochondrial antiviral signaling protein; MDA5: melanoma differentiation-associated gene-5; MyD88: myeloid differentiation primary response 88; RIG-I: RNA sensors retinoic acid-inducible gene I; TBK: TANK-binding kinase; TLR: Toll-like receptor; TRAF: tumor necrosis factor receptor-associated factor; TRAM: TRIF-related adaptor molecule; TRIF: TIRAP inducing interferon β.

Figure 3

Mechanism of the NLRP3 inflammasome pathway. NLRP3 inflammasomes are formed by priming and activation signaling. In the priming signaling, several pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) bind to the pattern-recognition receptors (PRRs) such as Toll-like receptors and activate the NF-κB signaling pathway, which leads to the upregulation of NLRP3, pro-interleukin (IL)-1β, and pro-IL-18. In the activation signaling, various PAMPs, DAMPs, or intracellular changes induce the formation of the NLRP3 inflammasome composed of NLRP3 as a PRR, pro-caspase-1, and adapter proteins such as the apoptosis-associated speck-like protein containing a caspase recruitment domain that connects NLRP3 and pro-caspase-1. Then, the inflammasome complex activates pro-caspase-1. The activated caspase-1 cleaves the pro-IL-1β and pro-IL-18 into IL-1β and IL-18, which are biologically active forms. Abbreviations: ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; DAMP: danger-associated molecular pattern; IL: interleukin; NF-κB: nuclear factor kappa B; NLRP3: NOD-like receptor family pyrin domain containing 3; TLR: Toll-like receptor.