A20 Inhibits Intraocular Inflammation in Mice by Regulating the Function of CD4+T Cells and RPE Cells

Hu, Jianping; Yi, Shenglan; Wang, Chaokui; Zhang, Yiting; Tang, Jihong; Huang, Xinyue; Yang, Lu; Yang, Jinglu; Li, Hong

doi:10.3389/fimmu.2020.603939

Cited by 9 publications

(8 citation statements)

References 58 publications

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“…Then, EAU mice were fed a special LCA diet (0.01%) or normal diet. Clinical manifestations and histopathological changes in the mice were evaluated as previously described 1 .…”

Section: Methodsmentioning

confidence: 99%

“…The PrimeScript RT reagent kit (Takara, Dalian, China) was used to synthesize cDNA from the RNA. The resultant DNA was amplified by real-time PCR as previously reported 1 . The sequences of the primers used in this study are shown in Table S2 .…”

Section: Methodsmentioning

confidence: 99%

“…The integrity of the BRB was evaluated using Evans blue (Sigma-Aldrich, MO, USA) as previously described 1 . The flat-placed retina was observed using a fluorescence microscope.…”

Section: Methodsmentioning

confidence: 99%

“…Uveitis is an autoimmune inflammatory disease marked by inflammation of intraocular entities 1 . Vogt-Koyanagi-Harada (VKH) syndrome and Behcet's disease (BD) are the most common forms of uveitis in China 2 .…”

Section: Introductionmentioning

confidence: 99%

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Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Hu¹,

Zhang²,

Yi³

et al. 2022

Int. J. Biol. Sci.

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Dendritic cells (DCs) are the major antigen-presenting cells and play an important role in autoimmune uveitis. Emerging evidence suggests that bile acids (BAs) regulate DCs maturation. However, the underlying mechanisms by which BAs regulate the function of DCs still need to be clarified. Here, we demonstrate that lithocholic acid (LCA) inhibits the production of pro-inflammatory cytokines and the expression of surface molecules in bone marrow-derived dendritic cells (BMDCs). LCA attenuates the severity of EAU by modulating the maturation of splenic CD11C + MHCII high DCs. Notably, Takeda G-protein coupled receptor 5 (TGR5) deficiency partially reverses the inhibitory effect of LCA on DCs in vitro and in vivo . TGR5 activation also downregulates the NF-κB and MAPK pathways by inhibiting glutathione production and inducing oxidative stress in DCs, which leads to apoptosis and autophagy in DCs. In addition, LCA or INT-777 treatment increases the TGR5 expression in monocyte-derived dendritic cells (MD-DCs) of patients with active BD, whereas both LCA and TGR5 agonists inhibit the activation of MD-DCs. These results suggest that LCA and TGR5 agonists might be potential therapeutic drugs for the treatment of autoimmune uveitis.

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“…Then, EAU mice were fed a special LCA diet (0.01%) or normal diet. Clinical manifestations and histopathological changes in the mice were evaluated as previously described 1 .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The integrity of the BRB was evaluated using Evans blue (Sigma-Aldrich, MO, USA) as previously described 1 . The flat-placed retina was observed using a fluorescence microscope.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Hu¹,

Zhang²,

Yi³

et al. 2022

Int. J. Biol. Sci.

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“…A20-dependent downregulation of NF-κB-mediated inflammation is further underlined by the fact that NF-κB activity is negatively regulated by A20 overexpression in mice. In addition, patients with an active autoimmune phenotype due to Behcet’s disease reveal a decreased expression of A20 in CD4+ T cells [ 72 ].…”

Section: Ubiquitin and Ubiquitin-like Proteins In T-lymphocytesmentioning

confidence: 99%

Recycling and Reshaping—E3 Ligases and DUBs in the Initiation of T Cell Receptor-Mediated Signaling and Response

Cammann

Israël

Slevogt

et al. 2022

IJMS

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T cell activation plays a central role in supporting and shaping the immune response. The induction of a functional adaptive immune response requires the control of signaling processes downstream of the T cell receptor (TCR). In this regard, protein phosphorylation and dephosphorylation have been extensively studied. In the past decades, further checkpoints of activation have been identified. These are E3 ligases catalyzing the transfer of ubiquitin or ubiquitin-like proteins to protein substrates, as well as specific peptidases to counteract this reaction, such as deubiquitinating enzymes (DUBs). These posttranslational modifications can critically influence protein interactions by targeting proteins for degradation by proteasomes or mediating the complex formation required for active TCR signaling. Thus, the basic aspects of T cell development and differentiation are controlled by defining, e.g., the threshold of activation in positive and negative selection in the thymus. Furthermore, an emerging role of ubiquitination in peripheral T cell tolerance has been described. Changes in the function and abundance of certain E3 ligases or DUBs involved in T cell homeostasis are associated with the development of autoimmune diseases. This review summarizes the current knowledge of E3 enzymes and their target proteins regulating T cell signaling processes and discusses new approaches for therapeutic intervention.

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A20 intrinsically influences human effector T‐cell survival and function by regulating both NF‐κB and JNK signaling

Dabbah‐Krancher,

Ruchinskas,

Kallarakal

et al. 2024

Eur J Immunol

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A20 is a dual‐function ubiquitin‐editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T‐cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T‐cell function remain unclear. TCR engagement triggers the assembly of the CARD11‐BCL10‐MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF‐κB and c‐Jun/AP‐1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF‐κB and JNK. Utilizing a novel set of A20 mutants in NF‐κB and AP‐1‐driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF‐κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL‐9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation‐induced cell death and increased sensitivity to cytokine withdrawal‐induced death. These findings demonstrate the importance of A20 in maintaining T‐cell homeostasis via negative regulation of both NF‐κB and JNK signaling.

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A20 Inhibits Intraocular Inflammation in Mice by Regulating the Function of CD4+T Cells and RPE Cells

Cited by 9 publications

References 58 publications

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Recycling and Reshaping—E3 Ligases and DUBs in the Initiation of T Cell Receptor-Mediated Signaling and Response

A20 intrinsically influences human effector T‐cell survival and function by regulating both NF‐κB and JNK signaling

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