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

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.

Multi-Omic Temporal Landscape of Plasma and Synovial Fluid-Derived Extracellular Vesicles Using an Experimental Model of Equine Osteoarthritis

“…Coagulation factor XIII A chain promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. Macrophages in the synovium are one of the sources of Coagulation factor XIII A [54]. Interestingly, the plasma concentration levels of this protein were associated with inflammatory arthritis and cartilage breakdown [55].…”

Tumor Necrosis Factor and Interleukin-1β Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation

“…RNA library preparation, sequencing, mapping, and gene-expression analysis were performed using DNAFORM (Yokohama, Kanagawa, Japan), as previously reported [ 24 ]. Gene expression was normalized to that of housekeeping genes.…”

“…Fluorescent IHC staining was conducted for FFPE synovial tissues collected from RA and OA specimens, as previously reported [ 24 ]. The following primary antibodies were used: anti-NRP1 antibody (rabbit monoclonal, clone EPR3113; Abcam, Cambridge, UK), anti-NRP2 antibody (rabbit monoclonal, clone D39A5; Cell Signaling Technology, Tokyo, Japan), anti-human cadherin-11 (CDH11) antibody (goat polyclonal; R&D Systems Inc.), anti-ACE2 antibody (rabbit polyclonal; Bioss Antibodies Inc., Woburn, MA, USA), and anti-TMPRSS2 antibody (rabbit polyclonal; Proteintech, Tokyo, Japan).…”

New Potentiality of Bioactive Substances: Regulating the NLRP3 Inflammasome in Autoimmune Diseases

“…This heightened release of inflammatory cytokines contributes to the degradation of connective tissues within the joints. Activated fibroblasts can also secrete chemokines and growth factors to recruit monocytes and promote their proliferation [112]. Therefore, there is a reciprocal interaction between FLS and monocytes/macrophages mediated by the NLRP3 inflammasome [113].…”