Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.00958
Keywords
RA; FLS; CRP; CD32; CD64; p38; NF-kappa B
Categories
Funding
- National Natural Science Foundation of China [81974253]
- Natural Science Foundation of Guangdong Province
- Shenzhen Science and Technology Plan of Basic Research Projects [2019A1515011112, JCYJ20170307112009204, JCYJ20170306161757367, JCYJ20170815090309586]
- Traditional Chinese Medicine Bureau of Guangdong Province [20183011]
- Research Grants Council of Hong Kong [GRF 14121816, 14163317, 14117418, 14104019, R4012-18F, C7018-16G]
- Lui Che Woo Institute of Innovative Medicine (CARE)
- Shenzhen Municipal Health Commission [SZSM201612009, SZSM201612061, SZWG2018009]
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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-kappa B or p38 pathways as blockade of CRP-CD32-NF-kappa B 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-kappa B signaling.
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