Hypoxia‐inducible factor‐1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis

Hu, Fanlei; Liu, Hongjiang; Xu, Liling; Li, Yingni; Liu, Xu; Shi, Lianjie; Su, Yin; Qiu, Xiaoyan; Zhang, Xia; Yang, Yuqin; Zhang, Jian; Li, Zhanguo

doi:10.1002/eji.201545784

Cited by 72 publications

(55 citation statements)

References 22 publications

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“…For example, the hypoxic conditions in RA synovium lead to the local production by FLS of hypoxia-inducible factor-1alpha, which alters FLS gene expression in multiple ways relevant to the pathogenesis of RA[104], including augmentation of production of pro-inflammatory cytokines and of interactions of FLS with both T and B cells. The pathogenesis of RA does not reflect the actions of any one cell lineage, but rather the complex interactions between all cell populations in RA synovium, mediated by both direct cell-cell contact and by molecules that are secreted or shed by the various types of synovial cells.…”

Section: Resultsmentioning

confidence: 99%

Synovial cellular and molecular markers in rheumatoid arthritis

2017

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Summary The profound alterations in the structure, cellular composition and function of synovial tissue in rheumatoid arthritis (RA) are the basis for the persistent inflammation and cumulative joint destruction that are hallmarks of this disease. In RA the synovium develops characteristics of a tertiary lymphoid organ, with extensive infiltration of lymphocytes and myeloid cells. Concurrently the fibroblast-like synoviocytes undergo massive hyperplasia and acquire a tissue-invasive phenotype. In this review we summarize key components of these processes, focusing on recently-described roles of selected molecular markers of these cellular components of RA synovitis.

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Section: Resultsmentioning

confidence: 99%

Synovial cellular and molecular markers in rheumatoid arthritis

2017

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“…HIF1α, a transcription factor that responds to reduced oxygen tension, is believed to have a central role in adaption to the hypoxic environment. Accumulating evidence proved that hypoxia and HIF1α regulate a number of pathophysiological characteristics of RA, including synovitis, angiogenesis, cartilage degradation and bone erosion . HIF1α has also been supposed to be a potential therapeutic target for RA .…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence proved that hypoxia and HIF1a regulate a number of pathophysiological characteristics of RA, including synovitis, angiogenesis, cartilage degradation and bone erosion. 30,32,39,40 HIF1a has also been supposed to be a potential therapeutic target for RA. 41 In the present study, we found inhibiting HIF1a significantly decreased the production of citrullinated F I G U R E 2 Hypoxia increases the production of PAD2 and citrullinated proteins in HFLS.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces production of citrullinated proteins in human fibroblast‐like synoviocytes through regulating HIF1α

Sun

et al. 2018

Scand J Immunol

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Hypoxia is a prominent microenvironment feature in a range of disorders including cancer, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel disease (IBD), infection and obesity. Hypoxia promotes biological functions of fibroblast-like synoviocytes via regulating hypoxia-inducible factor 1α (HIF1α). Dysregulated protein citrullination in RA drives the production of antibodies to citrullinated proteins, a highly specific biomarker of RA. However, the mechanisms promoting citrullination in RA are not yet fully elucidated. In this study, we investigated whether pathophysiological hypoxia as found in the rheumatoid synovium modulates the citrullination in human fibroblast-like synoviocytes (HFLS). Here, we found that peptidylarginine deiminase 2 (PAD2) and citrullinated proteins were increased in HFLS after exposure to hypoxia. Moreover, knocking down HIF1α by HIF1α siRNA ameliorated the expression of PAD2 and citrullinated proteins. Collectively, this study provides a new mechanism involved in generating citrullinated proteins: hypoxia promotes citrullination and PAD production in HFLS. Concurrently, we also proposed a novel hypoxia involved mechanism in RA pathogenesis. This study deepens our understanding of the role of hypoxia in the pathogenesis of RA and provides a potential therapeutic strategy for RA.

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“…On the other hand, there is evidence showing that HIF-1 α upregulates the expression of inflammatory cytokines including IFN- γ in synovial fibroblast of RA patients [23]. In this sense, IFN γ has been associated with more severe forms of SS, characterized by high grade infiltration of lymphocytes, macrophages, and dendritic cells as well as with gastric NHL lymphomas [24].…”

Section: Discussionmentioning

confidence: 99%

HIF1A(rs11549465) andAKNA(rs10817595) Gene Polymorphisms Are Associated with Primary Sjögren’s Syndrome

Hernández-Molina

Rodríguez-Pérez

Fernández‐Torres

et al. 2017

BioMed Research International

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Objective. To evaluate the allele and genotype frequencies of polymorphic sites of HIF1A and ANKA genes in primary Sjögren's syndrome (pSS). Methods. We included 110 patients with pSS and 141 ethnically matched healthy controls. Three HIF1A gene polymorphisms (Pro582Ser, Ala588Thr, and C191T) and two AKNA gene polymorphisms (−1372C>A and Pro624Leu) were genotyped using TaqMan probes in a Real-Time PCR instrument. Associations between pSS and genotypes, alleles, and inheritance models of the SNPs of interest were evaluated by logistic regression adjusted by age and gender. Results. The C/T genotype and the T allele of the HIF1A Pro582Ser polymorphism protected against pSS (OR = 0.22; 95% CI = 0.09–0.52; P < 0.01; OR = 0.26; 95% CI = 0.12–0.58; P < 0.01, resp.), whereas under a recessive model adjusted by age and gender, the AKNA −1372C>A polymorphism A/A genotype was associated with an increased risk of pSS (OR = 2.60; 95% CI = 1.11–6.12; P = 0.03). Conclusions. We identified HIF1A Pro582Ser T allele and C/T genotype as well as AKNA −1372C>A polymorphism A/A genotype as genetic factors associated with pSS. Further studies in other populations are needed to validate our findings and research is warranted in order to shed some light on their functional implications across biological pathways in this disease.

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Hypoxia‐inducible factor‐1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis

Abstract: Keywords: B cell r Hypoxia-inducible factor-1α r Rheumatoid arthritis r Synovial fibroblast r T cell Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 72 publications

References 22 publications

Synovial cellular and molecular markers in rheumatoid arthritis

Synovial cellular and molecular markers in rheumatoid arthritis

Hypoxia induces production of citrullinated proteins in human fibroblast‐like synoviocytes through regulating HIF1α

HIF1A(rs11549465) andAKNA(rs10817595) Gene Polymorphisms Are Associated with Primary Sjögren’s Syndrome

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