Autoimmune epithelitis (Sjögren's syndrome); the impact of metabolic status of glandular epithelial cells on auto-immunogenicity. (November 2019)

• Record Type: Journal Article
• Authors: Katsiougiannis, Stergios; Tenta, Roxane; Skopouli, Fotini N.
• Is Part Of: Journal of autoimmunity. Volume 104(2019)
• Publication Date: 2019-11
• Subjects: SS Sjögren's syndrome -- ER Endoplasmic Reticulum -- SGEC Salivary Gland Epithelial Cells -- XBP-1 X-box binding protein-1 -- AMPK 5′ adenosine monophosphate-activated protein kinase -- PPAR peroxisome proliferator-activated receptors -- TCR T-cell receptor -- OXPHOS Oxidative phosphorylation -- Teff effector T cells -- Treg T regulatory cells -- mTORC1 mammalian target of rapamycin complex 1 -- GRP78/BiP 78 kDa glucose-regulated protein -- UPR Unfolded Protein Response -- ERdj ER-localized DnaJ proteins -- ATP Adenosine triphosphate -- TEM transmission electron microscopy -- LSG Labial Salivary Gland -- ATF6α Activating transcription factor 6 α -- STING stimulator of interferon genes -- LC3 microtubule-associated protein 1 light chain 3 -- 3-MA 3-Methyladenine -- TG thapsigargin -- HSG human submandibular gland cell line -- IRF Interferon regulatory factor -- IFN Interferon -- IL-6 Interleukin-6 -- IL-4 Interleukin-4 -- MHC Major histocompatibility complex -- NOD non-obese diabetic mice -- TNF-α Tumor Necrosis Factor α; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.102335
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: It is well established that distinct cell metabolic alterations strongly contribute to the modulation of innate and adaptive immune responses. In the past decade the term immunometabolism has been introduced to describe the intracellular metabolic shifts of immune cells that lead to alterations of their functions. The pathogenesis of Sjögren's syndrome (SS), also referred to as autoimmune epithelitis, is not completely understood, but strong evidence supports the central role of the salivary glandular epithelial cells which are the target cells in the initiation of the autoimmune responses. Moreover, the altered epithelial functional phenotype, observed in the salivary gland lesion, may explain their disturbed secretory as well as immunoregulatory functions. From an immunometabolic perspective we have focused our studies on the endoplasmic reticulum (ER) of the salivary gland epithelial cells (SGEC) and the implication of its altered functions in the immunogenicity of these cells in SS. We showed that ER of SGEC in SS patients in situ is stressed and extensively dilated. Using salivary gland cell cultures, we studied in vitro the effect of ER stress on the metabolic behavior and viability of the cells. ER stress induced by thapsigargin increased spliced X-box binding protein-1 (XBP-1, transcription factor that increases the transcription of UPR target genes) levels in a time-dependent manner followed by autophagy and resulted to cell apoptosis. In apoptotic cells, we observed that the autoantigens Ro52 and La were redistributed in apoptotic blebs. During the induction of ER stress autophagy rescued the cells from apoptosis acting as a protective mechanism. We have also shown that adiponectin, a multifunctional hormone, is upregulated in the SGEC of SS patients acting in an autocrine or paracrine manner in the same cells. Adiponectin through activation of AMPK, the major sensor for cell energy demands, protected SGEC from apoptosis. Our results in combination with the work of others indicate that any effort of cell adaptation to ER stress may up regulate a proinflammatory milieu. This enhances the notion that metabolic alterations of the targeted epithelial cells in SS, independently of the cause, may induce an immunogenic phenotype. Therefore, SGEC have the potential to directly regulate susceptibility to and/or severity of autoimmune responses. Since adiponectin plays a vital role in the viability of SGEC through phosphorylation of AMPK, therapeutic interventions using PPAR agonists that upregulate adiponectin and concomitantly modify the energy metabolism, may be promising candidates for therapeutic intervention in SS. Highlights: Salivary gland epithelial cells (SGEC) are metabolically imbalanced in Sjögren's syndrome (SS). Endoplasmic reticulum of SGEC is stressed in SS. ER stress induces autophagy and immunogenic apoptosis. Adiponectin conveys antiapoptotic effects through AMPK phosphorylation. Peroxisome proliferator-activated receptors upregulate adiponectin secretion and may be used as therapeutic targets in SS.