May critical molecular cross-talk between indoleamine 2,3-dioxygenase (IDO) and arginase during human aging be targets for immunosenescence control?
Tóm tắt
This study aimed to identify novel plasma metabolic signatures with possible clinical relevance during the aging process. A biochemical quantitative phenotyping platform, based on targeted electrospray ionization tandem mass spectrometry technology, was used for the identification of any eventual perturbed biochemical pathway by the aging process in prospectively collected peripheral blood plasma from 166 individuals representing the population of São Paulo city, Brazil. Indoleamine 2,3-dioxygenase (IDO) activity (Kyn/Trp) was significantly elevated with age, and among metabolites most associated with elevations in IDO, one of the strongest correlations was with arginase (Orn/Arg), which could also facilitate the senescence process of the immune system. Hyperactivity of IDO was also found to correlate with increased blood concentrations of medium-chain acylcarnitines, suggesting that deficiencies in beta-oxidation may also be involved in the immunosenescence process. Finally, our study provided evidence that the systemic methylation status was significantly increased and positively correlated to IDO activity. In the present article, besides identifying elevated IDO activity exhibiting striking parallel association with the aging process, we additionally identified increased arginase activity as an underlying biochemical disturbance closely following elevations in IDO. Our findings support interventions to reduce IDO or arginase activities in an attempt to preserve the functionality of the immune system, including modulation of myeloid-derived suppressor cells (MDSCs), T cells, macrophages, and dendritic cells’ function, in old individuals/patients.
Tài liệu tham khảo
Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immun Ageing. 2019. https://doi.org/10.1186/s12979-019-0164-9.
Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007. https://doi.org/10.1111/j.1365-2567.2007.02555.x.
Ventura MT, Casciaro M, Gangemi S, Buquicchio R. Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin Mol Allergy. 2017. https://doi.org/10.1186/s12948-017-0077-0.
Aiello A, Farzaneh F, Candore G, et al. Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front Immunol. 2019. https://doi.org/10.3389/fimmu.2019.02247.
Vetrano DL, Triolo F, Maggi S, Malley R, Jackson TA, Poscia A, et al. Fostering healthy aging: the interdependency of infections, immunity and frailty. Ageing Res Rev. 2021. https://doi.org/10.1016/j.arr.2021.101351.
Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018. https://doi.org/10.1038/s41574-018-0059-4.
Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and Inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 2018. https://doi.org/10.3389/fimmu.2017.01960.
Pawelec G. Age and immunity: what is “immunosenescence”? Exp Gerontol. 2018. https://doi.org/10.1016/j.exger.2017.10.024.
da Silva I, et al. Inborn-like errors of metabolism are determinants of breast cancer risk, clinical response and survival: a study of human biochemical individuality. Oncotarget. 2018. https://doi.org/10.18632/oncotarget.25839.
da Silva IDCG, Levatti EVC, Pedroso AP, et al. Biochemical Phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease. Sci Rep. 2020. https://doi.org/10.1038/s41598-020-75862-4.
Altmaier E, et al. Bioinformatics analysis of targeted metabolomics--uncovering old and new tales of diabetic mice under medication. Endocrinology. 2008. https://doi.org/10.1210/en.2007-1747.
Bartel J, et al. The human blood Metabolome-Transcriptome Interface. PLoS Genet. 2015. https://doi.org/10.1371/journal.pgen.1005274.
Gieger C, Geistlinger L, Altmaier E, et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet. 2008;4(11):e1000282. https://doi.org/10.1371/journal.pgen.1000282.
Illig T, et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010. https://doi.org/10.1038/ng.507.
Suhre K, Shin SY, Petersen AK, et al. Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011. https://doi.org/10.1038/nature10354.
Chong J, et al. MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinformatics. 2019. https://doi.org/10.1002/cpbi.86.
Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009. https://doi.org/10.1038/nri2506.
Murray PJ. Amino acid Auxotrophy as immunological control nodes. Nat Immunol. 2016;17:132.
Breda CNS, Davanzo GG, Basso PJ, Saraiva Câmara NO, Moraes-Vieira PMM. Mitochondria as central hub of the immune system. Redox Biol. 2019;26:101255.
Mondanelli G, Iacono A, Allegrucci M, Puccetti P, Grohmann U. Immunoregulatory interplay between arginine and tryptophan metabolism in health and disease. Front Immunol. 2019. https://doi.org/10.3389/fimmu.2019.01565.
Grzywa TM, Sosnowska A, Matryba P, et al. Myeloid cell-derived Arginase in cancer immune response. Front Immunol. 2020. https://doi.org/10.3389/fimmu.2020.00938.
Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013. https://doi.org/10.1084/jem.20130066.
Timosenko E, Hadjinicolaou AV, Cerundolo V. Modulation of cancer-specific immune responses by amino acid degrading enzymes. Immunotherapy. 2017. https://doi.org/10.2217/imt-2016-0118.
O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016. https://doi.org/10.1038/nri.2016.70.
Pertovaara M, Raitala A, Lehtimäki T, et al. Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mech Ageing Dev. 2006. https://doi.org/10.1016/j.mad.2006.01.020.
Kouidhi S, Elgaaied AB, Chouaib S. Impact of metabolism on T-cell differentiation and function and cross talk with tumor microenvironment. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.00270.
Munder M. Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol. 2009. https://doi.org/10.1111/j.1476-5381.2009.00291.x.
Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64:5839.
Rath M, Müller I, Kropf P, Closs EI, Munder M. Metabolism via Arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol. 2014. https://doi.org/10.3389/fimmu.2014.00532.
Gupta S, Ahmad N, Marengo SR, Maclennan GT, Greenberg NM, Mukhtar H. Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice. Cancer Res. 2000;60:5125.
Oberlies J, Watzl C, Giese T, et al. Regulation of NK cell function by human granulocyte arginase. J Immunol. 2009. https://doi.org/10.4049/jimmunol.0803523.
Mondanelli G, Bianchi R, Pallotta MT, et al. A relay pathway between arginine and tryptophan metabolism confers immunosuppressive properties on dendritic cells. Immunity. 2017. https://doi.org/10.1016/j.immuni.2017.01.005.
Eleftheriadis T, Yiannaki E, Antoniadi G, et al. Plasma indoleamine 2,3-dioxygenase and arginase type I may contribute to decreased blood T-cell count in hemodialysis patients. Ren Fail. 2012. https://doi.org/10.3109/0886022X.2012.713297.
Auclair Y, Richard S. The role of arginine methylation in the DNA damage response. DNA Repair (Amst). 12(7):459–65. https://doi.org/10.1016/j.dnarep.2013.04.006 Epub 2013 May 17. PMID: 23684798 (2013).
Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S, et al. TDRD3 is an effector molecule for arginine-methylated histone marks. Mol Cell. 2010. https://doi.org/10.1016/j.molcel.2010.11.024.
Parry RV, Ward SG. Protein arginine methylation: a new handle on T lymphocytes? Trends Immunol. 2010;31:164.
Komrokji RS, Wei S, Mailloux AW, et al. A phase II study to determine the safety and efficacy of the Oral inhibitor of Indoleamine 2,3-Dioxygenase (IDO) enzyme INCB024360 in patients with Myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk. 2019. https://doi.org/10.1016/j.clml.2018.12.005.
Salminen A, Kaarniranta K, Kauppinen A. Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency. Cell Mol Life Sci. 2019. https://doi.org/10.1007/s00018-019-03048-x.
Bueno V, Sant'Anna OA, Lord JM. Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease. Age (Dordr). 2014. https://doi.org/10.1007/s11357-014-9729-x.
Stout RD, Suttles J. Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev. 2005. https://doi.org/10.1111/j.0105-2896.2005.00260.x.
Mussai F, De Santo C, Abu-Dayyeh I, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood. 2013;122:749.