A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis

Guo, Na; Ye, Sheng; Zhang, Kui; Xl, Yu; Cui, Hong‐Yong; Yang, Xiang-Min; Peng, Lin; Lv, Miaomiao; Miao, Jinlin; Zhang, Yang; Han, Qing; Zhang, Rongguang; Chen, Zhi‐Nan; Zhu, Ping

doi:10.1038/s41423-018-0012-4

Cited by 28 publications

(23 citation statements)

References 48 publications

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“…CD147 also serves as a novel receptor on platelets that activates platelets and aggravates inflammation in monocytes ( Schmidt et al, 2008 ). Several studies have shown that CD147 is strongly involved in the development of various inflammatory diseases, such as COVID-19 ( Wang et al, 2020 ), rheumatoid arthritis ( Guo et al, 2019 ), and inflammatory bowel disease ( Xu et al, 2020 ). Our previous studies have shown that CD147 participates in reprogramming of glucose metabolism ( Huang et al, 2014 ) as well as in lipid metabolism ( Li J. et al, 2015 ) in hepatocellular carcinoma, including de novo lipogenesis and fatty acid-oxidation.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

Wang

Cui

et al. 2021

Front. Cell Dev. Biol.

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The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147-overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future.

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Section: Introductionmentioning

confidence: 99%

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

Wang

Cui

et al. 2021

Front. Cell Dev. Biol.

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“…The final sources of cGAMP for the activation of STING in T cells should differ according to the possibility (or not) of a direct infection of T cells by SARS-CoV-2 through CD147 or CD26. Such infection has not yet been demonstrated, but might be searched in subsets of activated T cells of severe COVID-19) ( Table 2 ), including memory T cells which upon activation exhibit much greater up-regulation of CD147 than naïve T cells ( 39 ) ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

et al. 2020

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Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.

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“…For example, during the development of RA, CD147 is involved in the activation of memory T cells and the activation of the NLRP3 inflammasomes induced by ACPAs. 28 , 29 More importantly, CD147 has also been identified as a signal receiver during immune modulation, especially in T-cell development and activation. 30 – 32 In our previous studies, we found that, in young mice, CD147 depletion in thymocytes (CD147 T-KO ) resulted in decreased thymus size, thymic cellularity loss, and diminished T-cell lineage cell numbers, which were accompanied by increases in the number of various lymphocyte populations with innate immunological functions, such as γδ T cells, NKT-like cells, and NK-like cells.…”

Section: Introductionmentioning

confidence: 99%

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

et al. 2020

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Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity. Here, we show that the loss of CD147 on T cells prevents thymic senescence, resulting in slowed shrinkage of the thymus with age and increased production of naive T cells. This phenotype is the result of slowing of the epithelial–mesenchymal transition (EMT) process in thymic epithelial cells (TECs), which eventually leads to reduced adipocyte accumulation. In an in vitro coculture system, we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-Smad2/FoxC2 signaling. Moreover, CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs. In the presence of TGFβ, Annexin A2 and E-cadherin colocalize on TECs. However, CD147 on T cells competitively binds to Annexin A2 on TECs, leading to the isolation of E-cadherin. Then, the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase, the phosphorylation of which was induced by TGFβ, and finally, p-E-cadherin is degraded. Thus, in the thymus, the interaction between T cells and TECs contributes to thymic involution with age. In this study, we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.

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A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis

Cited by 28 publications

References 48 publications

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

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