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

Zhengyu Fang,Jiyang Lv,Fubo Zhong,Qingxia Qin,Hui-Yao Lan,Guoyu Liu,Gengmin Zhou,Qingwen Wang,Meiying Wang,Juan He,Jing Wang,Yadan Zheng

doi:10.3389/fimmu.2020.00958

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.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarticular and symmetrical arthritis mainly affecting the facet joints and is a major cause leading to progressive joint destruction and functional impairment or disability
C-reactive protein (CRP) Is Produced Locally by FLSs in Synovial Tissues From Patients With RA. It is well-known that synovial fluid of RA patients has high concentration of CRP [14]
We found that CRP was highly expressed in the synovial tissues of RA patients but not in normal controls (Figure 1A)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarticular and symmetrical arthritis mainly affecting the facet joints and is a major cause leading to progressive joint destruction and functional impairment or disability. Elevated serum levels of C-reactive protein (CRP) have been shown to correlate with the disease activity in patients with RA [12]. In patients with RA, increased levels of CRP are found in the synovial fluid [13, 14], the source origin of CRP remains unclear. It is well-known that the interaction of CRP with Fc-γ receptors leads to the production of pro-inflammatory cytokines [15, 16].

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Results

Conclusion