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

  • Arthritis Rheumatol. 2020 Jun;72(6):1003-1012. doi: 10.1002/art.41195.
Qingqing Tian  1 ,  Han Zhao  1 ,  Hanzhi Ling  1 ,  Li Sun  2 ,  Chipeng Xiao  1 ,  Guoyu Yin  1 ,  Xiaobing Wang  2 ,  Gan Wu  1 ,  Chenglin Yang  3 ,  Mu Chen  1 ,  Shengwei Jin  4 ,  Xinyu Yang  1 ,  Jianguang Wang  1
Affiliations
  • 1. Wenzhou Medical University, Wenzhou, China.
  • 2. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3. Zhejiang University, Hangzhou, China.
  • 4. The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
PMID: 31876388 DOI: 10.1002/art.41195
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.

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