Inflammation and Regeneration (Jan 2023)

Expression of factor XIII originating from synovial fibroblasts and macrophages induced by interleukin-6 signaling

  • Hirofumi Watanabe,
  • Sho Mokuda,
  • Tadahiro Tokunaga,
  • Hiroki Kohno,
  • Michinori Ishitoku,
  • Kei Araki,
  • Tomohiro Sugimoto,
  • Yusuke Yoshida,
  • Toshihiro Yamamoto,
  • Mayuko Matsumoto,
  • Junya Masumoto,
  • Shintaro Hirata,
  • Eiji Sugiyama

DOI
https://doi.org/10.1186/s41232-022-00252-4
Journal volume & issue
Vol. 43, no. 1
pp. 1 – 15

Abstract

Read online

Abstract Background Blood coagulation factor XIII (FXIII) promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. However, its expression in cells or tissues and function, particularly factor XIII subunit B (FXIII-B), remains controversial. Hemorrhagic FXIII deficiency following anti-interleukin-6 (IL-6) receptor antibody treatment has been reported in patients with rheumatoid arthritis (RA). Patients receiving this biologics have reduced FXIII activity when compared to the activity in those treated with other biologics. The relationship between pro-inflammatory cytokines and FXIII expression remains unknown. Methods To investigate the expression pattern of FXIII in synovial tissues, immunohistochemistry, RT-qPCR, and western blotting were performed. FXIII-A expressed monocyte-derived macrophages were treated with recombinant IL-6 and anti-IL-6 receptor antibody. RNA sequencing of FXIII-B-overexpressing cells was performed to clarify the function of FXIII-B. Results The immunohistochemical analysis of synovial tissues revealed that factor XIII subunit A (FXIII-A) was expressed in M2 macrophages, and FXIII-B was expressed in fibroblast-like synoviocytes. IL-6 stimulation upregulated FXIII-A expression in IL-4-induced monocyte-derived macrophages, and the anti-IL-6 receptor antibody suppressed FXIII-A expression. FXIII-B was more abundantly secreted in the supernatant of fibroblast-like synoviocytes compared with that of other cells. RNA sequencing showed that FXIII-B elevated the expression of genes associated with anti-apoptotic molecules and chemokines. Conclusions Our findings highlight that synovial tissue is one of the sources of FXIII production. We also have demonstrated IL-6-dependent FXIII-A expression and the novel potential functions of FXIII-B.

Keywords