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3. Impaired T cell IRE1[alpha]/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction

Author

Smolgovsky, Sasha, Bayer, Abraham L., Kaur, Kuljeet, Sanders, Erin, Aronovitz, Mark, Filipp, Mallory E., Thorp, Edward B., Schiattarella, Gabriele G., Hill, Joseph A., Blanton, Robert M., Cubillos-Ruiz, Juan R., and Alcaide, Pilar

Subjects
Cardiac output -- Measurement -- Health aspects, Antigens -- Testing, Heart failure -- Risk factors -- Prevention, Physiology, Pathological -- Analysis, Health care industry
Abstract

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1[alpha]/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1[alpha]/ XBP1 axis was a T cell signature of HFpEF., Introduction Widely regarded as the greatest unmet need in cardiovascular medicine, heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous syndrome accounting for roughly 50% of HF [...]

Published
2023
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5. A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis

Author

Huang, Yuhsin Vivian, primary, Lee, Daniel, additional, Sun, Yin, additional, Chou, Harrison, additional, Xu, Bruce, additional, Lin, Zachary, additional, Branche, Corynn, additional, Bayer, Abraham L, additional, Waliany, Sarah, additional, Neal, Joel, additional, Wakelee, Heather, additional, Witteles, Ronald, additional, Nguyen, Patricia, additional, Graves, Edward E, additional, Alcaide, Pilar, additional, Berry, Gerald J., additional, Wu, Sean M., additional, and Zhu, Han, additional

Published
2024
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7. Impaired T cell IRE1α-XBP1 signaling directs inflammation in experimental Heart Failure with Preserved Ejection Fraction

Author

Smolgovsky, Sasha, primary, Bayer, Abraham L., additional, Kaur, Kuljeet, additional, Sanders, Erin, additional, Aronovitz, Mark, additional, Filipp, Mallory E., additional, Thorp, Edward B., additional, Schiattarella, Gabriele G., additional, Hill, Joseph A., additional, Blanton, Robert M., additional, Cubillos-Ruiz, Juan R., additional, and Alcaide, Pilar, additional

Published
2023
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12. Abstract P3077: Withdrawal Of High Fat Diet And L-NAME Dampens T Cell Activation And Ameliorates Pathology In Experimental Heart Failure With Preserved Ejection Fraction (HFPEF) Through Modulation Of The T Cell IRE1a-XBP1 Axis

Author

Smolgovsky, Sasha, primary, Bayer, Abraham, additional, kaur, Kuljeet, additional, Aronovitz, Mark, additional, Sanders, Erin, additional, Blanton, Robert M, additional, Thorp, Edward B, additional, Schiattarella, Gabriele G, additional, Hill, Joseph A, additional, Cubillos-Ruiz, Juan R, additional, and Alcaide, Pilar, additional

Published
2023
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13. Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Author

Lim, Pei Jin, Duarte, Tiago L., Arezes, João, Garcia-Santos, Daniel, Hamdi, Amel, Pasricha, Sant-Rayn, Armitage, Andrew E., Mehta, Hema, Wideman, Sarah, Santos, Ana G., Santos-Gonçalves, Andreia, Morovat, Alireza, Hughes, Jim R., Soilleux, Elizabeth, Wang, Chia-Yu, Bayer, Abraham L., Klenerman, Paul, Willberg, Christian B., Hartley, Richard C., Murphy, Michael P., Babitt, Jodie L., Ponka, Prem, Porto, Graça, and Drakesmith, Hal

Published
2019
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23. Endothelial STING controls Tcell transmigration in an IFN-I dependent manner

Author

Anastasiou, Marina, primary, Newton, Gail A., additional, Kaur, Kuljeet, additional, Carrillo-Salinas, Francisco J., additional, Smolgovsky, Sasha A., additional, Bayer, Abraham L., additional, Ilyukha, Vladimir, additional, Sharma, Shruti, additional, Poltorak, Alexander, additional, Luscinskas, Francis W., additional, and Alcaide, Pilar, additional

Published
2021
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24. Endothelial Bmp2 knockout exacerbates hemochromatosis in Hfe knockout mice but not Bmp6 knockout mice

Author

Xiao, Xia, Dev, Som, Canali, Susanna, Bayer, Abraham, Xu, Yang, Agarwal, Aneesh, Wang, Chia-Yu, and Babitt, Jodie L.

Subjects
Male, Mice, Knockout, congenital, hereditary, and neonatal diseases and abnormalities, animal structures, Bone Morphogenetic Protein 6, nutritional and metabolic diseases, Bone Morphogenetic Protein 2, biological factors, Article, Mice, embryonic structures, Animals, Female, Endothelium, Hemochromatosis, Hemochromatosis Protein
Abstract

Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain.We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes.These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.

Published
2020

28. Deletion of MyD88 in T-cells Improves Anti-Tumor Activity in Melanoma

Author

Bayer, Abraham L., Padilla-Rolon, Darwing, Smolgovsky, Sasha, Hinds, Philip, and Alcaide, Pilar

Abstract

Cytotoxic CD8+T-cells are central to the anti-tumor immune response by releasing cytotoxic granules that kill tumor cells. They are activated by antigen presenting cells, which become activated by DAMPs (damage associated molecular patterns) through MyD88 (myeloid differentiation response 88). However, the suppressive tumor microenvironment promotes T-cell tolerance to tumor antigens in part by enhancing the activity of immune checkpoint molecules that prevent CD8+T-cell activation and cytotoxicity. We recently reported that MyD88 limits CD4+T-cell activation during cardiac adaptation to stress and hypothesized that a similar mechanism exists in CD8+T-cells which could be modulated to improve anti-tumor immunity. We found that adoptive transfer of MyD88-/-CD8+T-cells in melanoma-bearing T-cell deficient mice resulted in slower tumor growth, greater intratumoral T-cell accumulation, and higher melanoma cell death compared to transfer of WT CD8+T-cells. These findings were also observed in T-cell specific MyD88-/-mice compared to WT littermates implanted with melanoma. Mechanistically, we found that deletion of MyD88 enhances CD8+T-cell activation and survival, and TCR induced degranulation of cytotoxic molecules, overall improving their killing of melanoma cells. This enhanced cytotoxicity was retained in mice bearing tumors expressing the specific antigen for which cytotoxic T-cells were restricted. Our results demonstrate a conserved mechanism for MyD88 in modulating CD8+T-cell activation and represent a novel target in improving cancer immunotherapy.

Published
2024
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32. A Modular Turn-On Strategy to Profile E2-Specific Ubiquitination Events in Living Cells.

Author

Hill CJ, Datta S, McCurtin NP, Kimball HZ, Kingsley MC, Bayer AL, Martin AC, Peng Q, Weerapana E, and Scheck RA

Subjects
Animals, Humans, Ubiquitination, Ubiquitin-Protein Ligases metabolism, Mammals metabolism, Ubiquitin-Conjugating Enzymes metabolism, Ubiquitin metabolism
Abstract

A cascade of three enzymes, E1-E2-E3, is responsible for transferring ubiquitin to target proteins, which controls many different aspects of cellular signaling. The role of the E2 has been largely overlooked, despite influencing substrate identity, chain multiplicity, and topology. Here we report a method-targeted charging of ubiquitin to E2 (tCUbE)-that can track a tagged ubiquitin through its entire enzymatic cascade in living mammalian cells. We use this approach to reveal new targets whose ubiquitination depends on UbcH5a E2 activity. We demonstrate that tCUbE can be broadly applied to multiple E2s and in different human cell lines. tCUbE is uniquely suited to examine E2-E3-substrate cascades of interest and/or piece together previously unidentified cascades, thereby illuminating entire branches of the UPS and providing critical insight that will be useful for identifying new therapeutic targets in the UPS., (© 2024 Wiley-VCH GmbH.)

Published
2024
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33. AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.

Author

McRee SK, Bayer AL, Pietruska J, Tsichlis PN, and Hinds PW

Abstract

Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer, due to its highly metastatic nature. Melanomas harboring oncogenic BRAF V600E mutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain whether individual isoforms play distinct or redundant roles in each step. We investigate the contribution of individual AKT isoforms to melanoma initiation using a novel mouse model of AKT isoform-specific loss in a murine melanoma model, and investigate tumor progression, maintenance, and metastasis among a panel of human metastatic melanoma cell lines using AKT-isoform specific knockdown studies. We elucidate that AKT2 is dispensable for primary tumor formation but promotes migration and invasion in vitro and metastatic seeding in vivo , while AKT1 is uniquely important for melanoma initiation and cell proliferation. We propose a mechanism whereby inhibition of AKT2 impairs glycolysis and reduces an EMT-related gene expression signature in PTEN-null BRAF-mutant human melanoma cells to limit metastatic spread. Our data suggest that elucidation of AKT2-specific functions in metastasis could inform therapeutic strategies to improve treatment options for melanoma patients.

Published
2023
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34. Endothelial STING controls T cell transmigration in an IFNI-dependent manner.

Author

Anastasiou M, Newton GA, Kaur K, Carrillo-Salinas FJ, Smolgovsky SA, Bayer AL, Ilyukha V, Sharma S, Poltorak A, Luscinskas FW, and Alcaide P

Subjects
Animals, Immunity, Innate, Intercellular Adhesion Molecule-1 immunology, Mice, Signal Transduction immunology, Tumor Necrosis Factor-alpha metabolism, Vascular Cell Adhesion Molecule-1 immunology, Interferon Type I immunology, Interferon Type I metabolism, Membrane Proteins immunology, Receptor, Interferon alpha-beta immunology, Receptor, Interferon alpha-beta metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transendothelial and Transepithelial Migration immunology
Abstract

The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING-/- mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING-/- T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell-expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α-stimulated STING-/- EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.

Published
2021
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