C-Reactive Protein Promotes the Activation of Fibroblast-Like Synoviocytes From Patients With Rheumatoid Arthritis.

Abstract

Objective: To evaluate the biological effect and mechanisms of C-reactive protein (CRP) on the activation of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). Study design: To understand if CRP is involved in RA, expression of CRP and its receptors CD32/64 was examined in synovial tissues from RA patients and normal controls. In vitro, the potential role and mechanisms of CRP in FLS proliferation and invasion, expression of pro-inflammatory cytokines, and activation of signaling pathways were investigated in both RA - FLS and a normal human fibroblast-like synoviocyte line (HFLS). Results: Compared to normal controls, synovial tissues from 21 RA patients exhibited highly activated CRP signaling, particularly by FLSs as identified by 65% of CRP-expressing cells being CRP+vimentin+ and CD32/64+vimentin+ cells. In vitro, FLSs from RA patients, but not HFLS, showed highly reactive to CRP by largely increasing proliferative and invasive activities and expressing pro-inflammatory cytokines and chemokines, including CCL2, CXCL8, IL-6, and MMP2/9. All these changes were blocked largely by a neutralizing antibody to CD32 and, to a less extent by the anti-CD64 antibody, revealing CD32 as a primary mechanism of CRP signaling during synovial inflammation. Further studies revealed that CRP also induced synovial inflammation differentially via CD32/CD64- NF-κB or p38 pathways as blockade of CRP-CD32-NF-κB signaling inhibited CXCL8, CCL2, IL-6, whereas CRP induced RA-FLS invasiveness through CD32-p38 and MMP9 expression via the CD64-p38-dependent mechanism. Conclusions: CRP signaling is highly activated in synovial FLSs from patients with RA. CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p38 and NF-κB signaling.

• Authors: Zhengyu Fang, Jiyang Lv, Jing Wang, Qingxia Qin, Juan He, Meiying Wang, Gengmin Zhou, Guoyu Liu, Fubo Zhong, Yadan Zheng, Hui-Yao Lan, Qingwen Wang
• Journal: Frontiers in immunology (Front Immunol) Vol. 11 Pg. 958 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 32508836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Fang, Lv, Wang, Qin, He, Wang, Zhou, Liu, Zhong, Zheng, Lan and Wang.

Chemical References

• CRP protein, human
• Cytokines
• NF-kappa B
• Receptors, IgG
• Receptors, Immunologic
• C-Reactive Protein
• p38 Mitogen-Activated Protein Kinases

Topics

• Adult
• Arthritis, Rheumatoid (metabolism, pathology)
• C-Reactive Protein (metabolism, pharmacology)
• Case-Control Studies
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Cytokines (metabolism)
• Female
• Humans
• Male
• Middle Aged
• NF-kappa B (metabolism)
• Phenotype
• Receptors, IgG (metabolism)
• Receptors, Immunologic (metabolism)
• Signal Transduction
• Synoviocytes (drug effects, metabolism, pathology)
• p38 Mitogen-Activated Protein Kinases (metabolism)