ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome

Dong, Xiwen; Zheng, Zhaohui; Peng, Lin; Fu, Xianghui; Li, Fanni; Jiang, Jian‐Li; Zhu, Ping

doi:10.1038/s41423-019-0201-9

Cited by 84 publications

(75 citation statements)

References 47 publications

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“…However, up to now, little is known about the effect of ACPA on the control of the NFKB pathway. Interestingly, recent investigations have demonstrated that the treatment of PBMCs-derived macrophages with ACPA induced the activation of the NFKB pathway and subsequently the induction of the NLRP3-inflammasome and the production of pro-inflammatory cytokines 41 . Mechanistically, it was demonstrated that ACPA induces the activation of the NFKB pathway through the induction of the interaction between CD147 and integrin β1 or ATGB1, which in turn activates the downstream Akt/NFKB signalling pathway, resulting in the upregulation of NLRP3 and pro-IL-1β expression and further NLRP3 inflammasome activation 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent investigations have demonstrated that the treatment of PBMCs-derived macrophages with ACPA induced the activation of the NFKB pathway and subsequently the induction of the NLRP3-inflammasome and the production of pro-inflammatory cytokines 41 . Mechanistically, it was demonstrated that ACPA induces the activation of the NFKB pathway through the induction of the interaction between CD147 and integrin β1 or ATGB1, which in turn activates the downstream Akt/NFKB signalling pathway, resulting in the upregulation of NLRP3 and pro-IL-1β expression and further NLRP3 inflammasome activation 41 . Considering these interesting findings, we decided to assess in the HFGP cohort if there was any correlation between the NFKB2 SNPs and pro-and anti-inflammatory cytokine production after stimulation of whole blood, PBMCs or monocyte-derived macrophages with LPS, PHA or Pam3Cys.…”

Section: Discussionmentioning

confidence: 99%

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NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

Sánchez-Maldonado

Martínez-Bueno

Canhão

et al. 2020

Sci Rep

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This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

Sánchez-Maldonado

Martínez-Bueno

Canhão

et al. 2020

Sci Rep

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“…Previous reports have also documented that outside-in signaling via b 1 -integrins including VLA-4 on monocytes can activate the NF-kB signaling pathway (16)(17)(18)(19). This in turn initiates the transcription of inflammatory genes (e.g., c-fos and c-jun) that promote expression of components of the NLRP3 inflammasome and pro-IL-1b, resulting in cellular conversion to an inflammatory phenotype (18,20). The mechanism underlying how integrins and other receptors that concentrate within lipid rafts at sites of focal adhesion participate in the conversion of arrested monocytes into inflammatory macrophages capable of producing TNF-a, IL-1b, and IL-6 within nascent plaques has not been established (21,22).…”

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confidence: 96%

“…We have previously reported that high affinity CD11c mechanotransduces the activation of kinase (i.e., phospho-Syk), resulting in the recruitment of cytoskeletal adaptor proteins paxillin and the consolidation of VLA-4 bound to VCAM-1 to support shearresistant monocyte arrest and the subsequent transendothelial migration (TEM) (15). Previous reports have also documented that outside-in signaling via b 1 -integrins including VLA-4 on monocytes can activate the NF-kB signaling pathway (16)(17)(18)(19). This in turn initiates the transcription of inflammatory genes (e.g., c-fos and c-jun) that promote expression of components of the NLRP3 inflammasome and pro-IL-1b, resulting in cellular conversion to an inflammatory phenotype (18,20).…”

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confidence: 99%

An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes

Hernandez

Foster

Soderberg

et al. 2020

The Journal of Immunology

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Intermediate monocytes (iMo; CD14 + CD16 +) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity b2-integrin (CD11c/CD18) that activates b1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk-and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-kB and production of IL-1b +. We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

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“…as a result of autoimmune activation, prolonged inflammation, cartilage deterioration, and bone destruction [2]. Innate and adaptive immune cells as well as synovial cells participate in RA pathogenesis [3,4]. Innate immune cells, such as macrophages and dendritic cells, facilitate the breakdown of immune tolerance.…”

Section: Introductionmentioning

confidence: 99%

Pulp stem cells with hepatocyte growth factor overexpression exhibit dual effects in rheumatoid arthritis

Dong¹,

Kong²,

Liu

et al. 2020

Stem Cell Res Ther

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Background: To investigate the therapeutic effect of human dental pulp stem cells (DPSCs) transfected with adenovirus expressing hepatocyte growth factor (HGF) in a mouse model of collagen-induced arthritis (CIA). Methods: DPSCs were modified with Ad-HGF to produce HGF-overexpressing DPSCs, DPSCs-HGF. In experimental mouse CIA model, DPSCs-HGF and DPSCs-Null (modified with Ad-Null) were engrafted via intravenously after disease onset, which was determined by the presence of joint swelling. The therapeutic effects on joints were evaluated at 49 days after collagen injection by histopathological analysis and microcomputed tomography imaging. The inflammatory cytokines were analyzed both in sera and joints via MILLIPLEX kit and immunohistochemical staining, respectively, and the regulatory T cells (Tregs) were analyzed in peripheral blood by using flow cytometry. Furthermore, primary fibroblast-like synoviocytes were isolated, colony formation analysis and FACS were performed to evaluate the effect of HGF on the proliferation and cell cycle of FLSs. Western blot assay was carried out to clarify the signal pathway of HGF-cMet. Results: We found that without HGF modification, DPSC transfusion was helpful in controlling autoimmune status, local synovitis, and bone erosion after intravenous administration. However, HGF-modified DPSCs have dual role in rheumatoid arthritis (RA). In the early phase, HGF overexpression inhibited RA progression by its immunosuppressive effects, while in the late phase, HGF promoted synovitis by activating fibroblast-like synoviocytes to produce pathogenic IL-6, accelerating cell proliferation and inducing apoptosis resistance via phosphorylating the c-Met/Akt pathway. The overall effect of HGF modification attenuated the therapeutic effect of DPSCs. Conclusions: Our study provides a comprehensive evaluation of the therapeutic effect of DPSCs in the mouse model and a primary answer to the divergence of whether HGF is harmful or helpful in RA.

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ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome

Cited by 84 publications

References 47 publications

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes

Pulp stem cells with hepatocyte growth factor overexpression exhibit dual effects in rheumatoid arthritis

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