TLR7 Signaling Drives the Development of Sjögren's Syndrome

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Yawen Wang - , Aix-Marseille Université, Université de Bordeaux, Institut national de la santé et de la recherche médicale (Author)
  • Annie Roussel-Queval - , Aix-Marseille Université (Author)
  • Lionel Chasson - , Aix-Marseille Université (Author)
  • Noël Hanna Kazazian - , Aix-Marseille Université (Author)
  • Laetitia Marcadet - , Aix-Marseille Université (Author)
  • Andrianos Nezos - , National and Kapodistrian University of Athens (Author)
  • Michael H Sieweke - , Chair of Stem Cell Research with focus on cell-based approaches to regenerative biomedicine, Aix-Marseille Université, Institut national de la santé et de la recherche médicale, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Author)
  • Clio Mavragani - , National and Kapodistrian University of Athens (Author)
  • Lena Alexopoulou - , Aix-Marseille Université (Author)

Abstract

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value.

Details

Original languageEnglish
Article number676010
JournalFrontiers in immunology
Volume12
Publication statusPublished - 24 May 2021
Peer-reviewedYes

External IDs

PubMedCentral PMC8183380

Keywords

Keywords

  • Adult, Aged, Animals, Chemokines/genetics, Cytokines/genetics, Female, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Pneumonia/etiology, Signal Transduction/physiology, Sjogren's Syndrome/etiology, Toll-Like Receptor 7/physiology