Targeting of janus kinases limits pro-inflammatory but also immunosuppressive circuits in the crosstalk between synovial fibroblasts and lymphocytes

Nina Yao, Theresa Tretter, Peter Kvacskay, Wolfgang Merkt, Norbert Blank, Hanns Martin Lorenz, Lars Oliver Tykocinski

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro-and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment.

Original languageEnglish
Article number1413
JournalBiomedicines
Volume9
Issue number10
DOIs
StatePublished - Oct 2021
Externally publishedYes

Keywords

  • BDMARDs
  • Baricitinib
  • JAK inhibitors
  • Janus kinases
  • Rheumatoid arthritis
  • Synovial fibroblasts
  • T helper cells
  • Tofacitinib
  • Upadacitinib

Fingerprint

Dive into the research topics of 'Targeting of janus kinases limits pro-inflammatory but also immunosuppressive circuits in the crosstalk between synovial fibroblasts and lymphocytes'. Together they form a unique fingerprint.

Cite this