PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke

Guo, Ying; Chen, X; Li, D; Liu, H; Ding, Yun; Han, Ranran; Shi, Yuan; Ma, Xiaofeng

doi:10.1111/cei.13132

Cited by 34 publications

(30 citation statements)

References 41 publications

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“…Studies have demonstrated IL-6 plays a prominent role in regulating the balance between Th17 cells and regulatory T cells [ 56 ], which affects inflammation. Inhibiting T lymphocyte infiltration and decreasing Th17 cells differentiation could provide neuroprotection of ischemic stroke [ 57 ]. It was also reported that IL-6 produced by mature adipocytes and fibroblast supports breast tumor growth and metastasis [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

et al. 2021

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Background Macrophages regulate the inflammatory response and affect re-endothelialization. Inflammation and macrophages play important roles in promoting tissue repair, but p38α mitogen-activated protein kinase's role in re-endothelialization is unknown. Methods and results Wire injuries of carotid arteries and Evans blue staining were performed in macrophage-specific p38α-knockout (p38α fl/fl LysMCre +/- ) mice and control mice (p38α fl/fl ). Re -endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38α fl/fl LysMCre +/- mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38α fl/fl LysMCre +/- mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38α fl/fl LysMCre +/- mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38α fl/fl mice in vivo . Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38α fl/fl LysMCre +/- mice. The mutation of either S544/S549 or T545/S549 sites could reduce the expression of IL-6 and the inhibition of MKL1 reduced the expression of IL-6 in vitro and promoted re-endothelialization in vivo . Conclusion p38α in macrophages aggravates injury of arteries by phosphorylating MKL1, and increasing IL-6 expression after vascular injury.

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Section: Discussionmentioning

confidence: 99%

p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

et al. 2021

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“…Finally, an excessive activity of immunoproteasomes may contribute to Th17/Treg disequilibrium in IgAN. It has been evidenced that immunoproteasome subunit coded by PSMB8 gene is necessary for Th17 differentiation and inhibits Treg differentiation [41, 42]. It was demonstrated that PBMC of IgAN patients had higher expression of PSMB8 gene [43, 44], especially those individuals with high proteinuria [43] or those experiencing greater annual loss of eGFR [45].…”

Section: Alterations Of T Cell Subpopulations In Iga Nephropathymentioning

confidence: 99%

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

et al. 2018

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Background Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN Methods We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells’ participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. Results We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. Conclusions T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.

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“…Furthermore, IP inhibition in preclinical animal models protected from colitis-associated cancer formation (18,19) exacerbated the pathogenesis of experimental systemic Candida albicans infection (20), protected from virus-induced myocarditis (21), and prevented organ rejection in transplantation (22)(23)(24). Two major pathways involved in disease development are affected by LMP7 inhibition, namely Th cell differentiation (15,(25)(26)(27)(28) and cytokine secretion (13,25,27,29,30). The LMP7/ LMP2-specific inhibitor ONX 0914 (25,31) strongly reduced the secretion of different proinflammatory cytokines of TCR-activated T cells and endotoxin-stimulated human PBMCs or mouse splenocytes (20,25,(29)(30)(31).…”

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confidence: 99%

Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion

Basler

Claus

Klawitter

et al. 2019

The Journal of Immunology

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MECL-1 (b2i), LMP2 (b1i), and LMP7 (b5i) are the proteolytically active subunits of the immunoproteasome (IP), a special type of proteasome mainly expressed in hematopoietic cells. Targeting the IP in autoimmune diseases proved to be therapeutically effective in preclinical mouse models. In endotoxin-stimulated human PBMCs, IP inhibition reduces the secretion of several proinflammatory cytokines, with the suppression of IL-23 being the most prominent. In this study, we investigated why the production of IL-23, a key mediator of inflammation in autoimmunity, is blocked when the IP is inhibited in LPS-stimulated human PBMCs. CD14 + monocytes could be identified as the main producers of IL-23 in LPS-stimulated PBMCs. We found that IP inhibition with the irreversible LMP7/LMP2 inhibitor ONX 0914 induced apoptosis in CD14 + monocytes, whereas CD4 + , CD3 + , CD19 + , and CD56 + cells remained unaffected. A high expression of IPs renders monocytes susceptible to IP inhibition, leading to an accumulation of polyubiquitylated proteins and the induction of the unfolded protein response. Similar to IP inhibition, inducers of the unfolded protein response selectively kill CD14 + monocytes in human PBMCs. The blockage of the translation in CD14 + monocytes protects these cells from ONX 0914-induced cell death, indicating that the IP is required to maintain protein turnover in monocytes. Taken together, our data reveal why IP inhibition is particularly effective in the suppression of IL-23-driven autoimmunity.

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PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke

Cited by 34 publications

References 41 publications

p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion

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