Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

Qin, Xianyun; Zhang, Yun-Long; Chi, Yafei; Yan, Bo; Zhang, Xiangjun; Li, Huihua; Liu, Ying

doi:10.1159/000487562

Cited by 28 publications

(33 citation statements)

References 30 publications

(49 reference statements)

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“…The subsequent enhanced GTP cyclohydrolase I degradation results in nitric oxide signaling pathway dysfunction [40]. Very recently, it was reported that Ang II regulates Th1 T cell differentiation through the activation of AT1R/PKA signaling pathway and the consequent increases in the activities and expression of proteasome catalytic subunits [41]. In our study, we demonstrated for the first time that Ang II activates ubiquitination-proteasome system, which promotes degradation of PPARγ.…”

Section: Discussionsupporting

confidence: 57%

The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

Sun

Bian

2019

Int. J. Biol. Sci.

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Evidence has documented local angiotensin II (Ang II) as a pro-oxidant and pro-inflammatory molecule contributes to progressive deterioration of organ function in diseases. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, plays crucial roles in protection against oxidative stress and inflammation. Ang II stimulation decreases PPARγ protein in multiple types of cells, while the regulatory role of Ang II on PPARγ is not clear. Here we show that Ang II down-regulated PPARγ in ECV304 cells through 2 actions, inducing nuclear export and loss of protein. The nuclear export of PPARγ occurred transiently in the early phase, while the reduction in PPARγ protein happened in the later phase and was more persistent. Both alterations in PPARγ were accompanied by the decrease in PPARγ-DNA binding activity. Reduction of PPARγ protein levels was also coupled with the inhibition of PPARγ target genes. In addition, activation of PPARγ by its ligand troglitazone could completely counteract both 2 actions of Ang II on PPARγ. Further studies demonstrated that the decline of PPARγ protein was in association with ubiquitin-proteasome-dependent degradation, which was supported by the increase in polyubiquitin-PPARγ conjugates and the inhibitory effect of lactacystin, a specific proteasome inhibitor, on the loss of PPARγ. Taken together, this study uncovers a novel means by which Ang II down-regulates PPARγ. This down-regulation disrupts nuclear PPARγ function, which may lead to the loss of beneficial effects of PPARγ in response to Ang II stress.

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Section: Discussionsupporting

confidence: 57%

The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

Sun

Bian

2019

Int. J. Biol. Sci.

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“…AT1R stimulation has been shown to play a role in the differentiation of CD4 + T cells into Th1 cell through the modulation of proteasome function; thus, RASi may inhibit this mechanism of CD4 + T cell antigenmediated activation. 38 The proportion of activated circulating CD4 + T cells may have been diminished as a result of reduced AngII; therefore, trafficking into the liver and tumor was profoundly affected, as it was reported during deoxycorticosterone acetate-salt hypertension. 39 RASi appears to not have a selective effect on the infiltration of CD8 + T cells into the liver; however, the significant increase in CD8 + lymphocytes into the tumor, particularly those that are identified as tissue resident (CD103 + ) and PD-1 + , may indicate a recently activated tumor-specific cytotoxic T cell population.…”

Section: Discussionmentioning

confidence: 94%

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

Ardila

Walsh

Fifis

et al. 2020

J Immunother Cancer

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BackgroundIt is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin–angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin–angiotensin system inhibitors (RASi).AimTo investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases.MethodsLiver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC).ResultsCaptopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets .ConclusionCaptopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.

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“…It is well known that immune and inflammatory cells, including macrophages, T cells and dendritic cells, play an important role in the development and progression of atherosclerosis [23,24]. The immunoproteasome is expressed constitutively in immune cells, and can be induced in immune and non-immune cells upon exposure to pro-inflammatory stimuli such as viruses, angiotensin II and high salt, thus contributes to the regulation of immuno-inflammatory diseases, including viral myocarditis, hypertrophic remodeling, atrial fibrillation and vascular cell apoptosis [15,16,18,[25][26][27][28]. Here, the results presented showed that β5i was upregulated in the atherosclerotic plaques of eKO mice (Figure 1); genetic ablation or inhibition of β5i reduced lesional accumulation of apoptotic cells but enhanced MERTK-mediated efferocytosis, therefore inhibited necrotic core formation and atherosclerosis progression (Figures 2-4).…”

Section: Discussionmentioning

confidence: 99%

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

Liao

Xie

Lin

et al. 2020

The Journal of Pathology

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The immunoproteasome contains three catalytic subunits (β1i, β2i and β5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between β5i and human atherosclerotic plaque instability; however, the causative role of β5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of β5i. We found that β5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). β5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase‐3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with β5i‐specific inhibitor PR‐957. Mechanistic studies in vitro revealed that β5i deletion reduced IκBα degradation and inhibited NF‐κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that β5i plays an important role in diet‐induced atherosclerosis by altering MERTK‐mediated efferocytosis. β5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

Cited by 28 publications

References 30 publications

The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

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