The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Kemp, Kyeorda; Lin, Zhenghong; Zhao, Fang; Gao, Beixue; Song, Jianxun; Zhang, Kezhong; Fang, Deyu

doi:10.1074/jbc.m113.493171

Cited by 49 publications

(58 citation statements)

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“…S1 A-E). Both of these drugs were used at concentrations that do not compromise cell viability or induce any other toxicity (21,34,35,(37)(38)(39)(40). Consistent with earlier reports, these IRE1 inhibitors had no effect on the kinase function of IRE1 (Fig.…”

Section: Resultssupporting

confidence: 83%

“…4C). Analogous experiments using 4μ8c in the same animal model [using previously published doses that showed no toxicity (33,37,40,48)] produced similar results (Fig. 4 D-F): 4μ8c treatment led to a significant reduction (45.2%; P < 0.001) in atherosclerotic lesion area in en face aorta preparations (Fig.…”

Section: Resultssupporting

confidence: 74%

“…Consistent with these observations, treatment with IRE1 inhibitors led to a marked suppression of hyperlipidemia-induced Th-1 immune responses in these mice. We observed no differences in T-cell numbers in adventia/lesions between the IRE1 inhibitor treatment and control groups, and previous studies have shown the IRE1 inhibitor used in this study does not affect Treg cells (33,37). Collectively, these findings show that prevention of inflammasome-associated cytokine production by IRE1 inhibitors in vivo has dramatic effects on counteracting atherosclerotic disease progression.…”

Section: Discussionsupporting

confidence: 67%

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Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

179

195

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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.endoplasmic reticulum stress | unfolded protein response | metaflammation | lipotoxicity | atherosclerosis C omplex molecular interactions between environment, diet, and genetics that take place at the metabolic and immune interface provoke a low-grade, chronic inflammatory responsemetaflammation-that engages cells of the immune system (macrophages, neutrophils, and lymphocytes) and metabolic tissues (adipocytes, hepatocytes, and pancreatic cells) (1). An important primer for metaflammation is chronic metabolic overloading of organelles, such as the endoplasmic reticulum (ER) and mitochondria, which results in impairment of their functions (2).The ER serves essential cellular functions that include the synthesis and folding of secreted and transmembrane proteins, calcium storage, and lipid synthesis for membrane biogenesis or energy storage. Disruption of any of these functions leads to ER stress and the subsequent activation of an elaborate network of adaptive responses, collectively known as the unfolded protein response (UPR) (3). The UPR reestablishes homeostasis through both transcriptional and translational layers of control. The UPR signals through three mechanistically distinct branches that are initiated by the ER-resident protein folding sensors inositolrequiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (3).IRE1 controls the phylogenetically most conserved branch of the UPR found from fungi to metazoans. It has an ER-lumenal sensor domain that recognizes unfolded peptides and cytosolic kinase and endoribonuclease (RNase) domains that relay the information to downstrea...

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Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 74%

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

179

195

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“…In Vitro Th17 Differentiation-Wild type and Sirt1-null bone marrow-derived DCs (2 ϫ 10 4 ) were plated into 96-well plate and activated with LPS (100 ng/ml) for 16 h as described (22). After washing DCs with PBS twice, CD4 ϩ T cells (2 ϫ 10 5 ) were added and activated with anti-CD3 (1 g/ml), recombinant human TGF␤ (2 ng/ml; Biolegend), recombinant mouse IL-6 (20 ng/ml, Biolegend), anti-IFN-␥, and anti-IL-4 (10 g/ml, Biolegend).…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Sirtuin 1 Deacetylates IRF1 Protein and Programs Dendritic Cells to Control Th17 Protein Differentiation during Autoimmune Inflammation

Yang

Lee

Gao

et al. 2013

Journal of Biological Chemistry

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Background:The roles of Sirt1 in regulating dendritic functions are not known. Results: Sirt1 deacetylates the IRF1 transcription factor to suppress IL-27 expression in dendritic cells, leading to elevated Th17 differentiation for inflammatory disease development. Conclusion: Sirt1 programs DC functions to promote Th17 differentiation and inflammation. Significance: This study defines a previously unappreciated inflammatory role of Sirt1 in dendritic cells.

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“…For the in vitro T cell activation analysis, naïve CD44 Lo CD62L hi naïve CD4 + T cells were sorted from the spleens of WT and KO mice, stained with CFSE and cultivated with anti-CD3 (1 μg/ml) plus anti-CD28 (1 μg/ml) or under each polarization condition as described (27). T cell proliferation was determined by flow cytometry analysis of CFSE dilution or 3H-thymidine incorporation.…”

Section: Methodsmentioning

confidence: 99%

The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation

Gao¹,

Kong²,

Zhang³

et al. 2017

The Journal of Immunology

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Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of Gcn5 (general control nonrepressed-protein 5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. Here we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production and Th1/Th17, but not Th2 and Treg differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the nuclear factor of activated T cells (NFAT) in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 (H3K9) acetylation to promote IL-2 production. T cell-specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence, Gcn5 may be an important new target for autoimmune disease therapy.

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The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Cited by 49 publications

References 50 publications

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Histone Deacetylase Sirtuin 1 Deacetylates IRF1 Protein and Programs Dendritic Cells to Control Th17 Protein Differentiation during Autoimmune Inflammation

The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation

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