Poly(ADP‐Ribose) Polymerase Enhances Infiltration of Mononuclear Cells in Primary Sjögren's Syndrome Through Interferon‐Induced Protein With Tetratricopeptide Repeats 1–Mediated Up‐Regulation of CXCL10

Abstract

Objective Mononuclear cell infiltration and type I interferon (IFN) system activation play an important role in primary Sjögren's syndrome (SS). We undertook this study to investigate the mechanism of poly(ADP‐ribose) polymerase family member 9 (PARP‐9) on mononuclear cell infiltration triggered by type I IFN. Methods A proteomic study was conducted in peripheral blood mononuclear cells from patients with primary SS (n = 30) and healthy controls (n = 30) to determine differentially expressed proteins (DEPs) (P < 0.05; fold change >1.20). Labial salivary glands (LSGs) were isolated for hematoxylin and eosin staining and immunohistochemical analysis. CD19+ B cells were purified by magnetic cell sorting for immunofluorescence staining, lentivirus–PARP‐9 transfection, and IFNα treatment experiments. PARP‐9 small interfering RNA (siRNA) and DTX3L siRNA were delivered into female NOD/LtJ female mice to determine their effect. Results The overexpression of PARP‐9 and CXCL10 as well as their colocalization was confirmed in primary SS. PARP‐9 levels in LSGs rose with increased Chisholm scores in patients with primary SS. PARP‐9 and DTX3L were present in the infiltrating mononuclear cells from salivary glands in female NOD/LtJ mouse models. Additionally, Ingenuity Pathway Analysis networks of DEPs demonstrated that PARP‐9, STAT1, and IFN‐induced protein with tetratricopeptide repeats 1 (IFIT‐1) participated in the IFN‐related pathway. Furthermore, PARP‐9 could up‐regulate the expression of IFIT1 and CXCL10 in B cells. Moreover, PARP‐9 and CXCL10 could be induced by IFNα in B cells. Conclusion This study is the first to implicate PARP‐9 as a regulator of infiltration of mononuclear cells in primary SS progression and to reveal that PARP‐9 increases CXCL10 expression through up‐regulating IFIT‐1, which is mediated by the phosphorylation of STAT1. PARP‐9 might therefore be a novel therapeutic target for primary SS.

IFIT Proteins Are Involved in CXCL10 Expression in Human Glomerular Endothelial Cells Treated with a Toll-Like Receptor 3 Agonist

“…The increase of CXCL10 mRNA was slower than those of IFIT1, IFIT2, and IFIT3 and reached maximum 16 h after the poly IC treatment. It has been reported that overexpression of IFIT1 upregulated CXCL10 expression in B cells [26]. In the present study, knockdown of IFIT1, IFIT2, or IFIT3 resulted in the decrease of CXCL10 expression induced by poly IC, suggesting that IFIT1, IFIT2, and IFIT3 positively regulate the expression of CXCL10 in GECs.…”

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

“…It consequently promotes the downstream gene expression of the Notch signaling pathway and ultimately accelerates the angiogenesis of endothelial cells ( Wang et al, 2020a ). In primary Sjogren’s syndrome, the DTX3L/BAL1 complex enhances the phosphorylation of STAT1 to upregulate IFN-induced protein with tetratricopeptide repeats 1 (IFIT-1) and increases the expression of chemokine (C–X–C motif) ligand 10 (CXCL10), thereby promoting the infiltration of mononuclear cells ( Tian et al, 2020 ).…”

Integrated Bioinformatics and Validation Reveal Potential Biomarkers Associated With Progression of Primary Sjögren’s Syndrome

“…MS4A1 has also been identified in a study published by Luo et al (15). CD19+ B cells are often used for the identification of pSS and have been widely verified as a diagnostic marker (61,62). CCL19 maybe involved in more sever forms of autoimmune diseases, such as rheumatoid arthritis (63).…”