{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:51:13Z","timestamp":1785423073937,"version":"3.56.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Centro de Investigaci\u00f3n Pr\u00edncipe Felipe"},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n, Spain","doi-asserted-by":"crossref","award":["SAF2014-51851-R"],"award-info":[{"award-number":["SAF2014-51851-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Conseller\u00eda Educaci\u00f3n Generalitat Valenciana","award":["PROMETEOII\/2014\/033"],"award-info":[{"award-number":["PROMETEOII\/2014\/033"]}]},{"name":"Conseller\u00eda Educaci\u00f3n Generalitat Valenciana","award":["PROMETEOII\/2018\/051"],"award-info":[{"award-number":["PROMETEOII\/2018\/051"]}]},{"name":"European Regional Development Funds"},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["BIO205-71658-R"],"award-info":[{"award-number":["BIO205-71658-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008054","name":"Fundaci\u00f3n Ram\u00f3n Areces","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008054","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE. Transcriptomic analysis supports the hypothesis of alternations in the Th1\/Th2 and Th17 lymphocytes cell populations as major drivers of MHE. Cluster analysis of serum molecules resulted in six groups of chemically similar compounds, suggesting that functional modules operate during the induction of MHE. Finally, the multi-omic integrative analysis suggested a relationship between cytokines CCL20, CX3CL1, CXCL13, IL-15, IL-22 and IL-6 with alteration in chemotaxis, as well as a link between long-chain unsaturated phospholipids and the increased fatty acid transport and prostaglandin production. We found altered immune pathways that may collectively contribute to the mild cognitive impairment phenotype in MHE. Our approach is able to combine extracellular and intracellular information, opening new insights to the understanding of the disease.<\/jats:p>","DOI":"10.1038\/s41598-020-80941-7","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T11:03:39Z","timestamp":1611227019000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients"],"prefix":"10.1038","volume":"11","author":[{"given":"Teresa","family":"Rubio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Felipo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Tarazona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Pastorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desamparados","family":"Escudero-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Tosca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amparo","family":"Urios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Conesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmina","family":"Montoliu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"80941_CR1","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1038\/nrn3587","volume":"14","author":"V Felipo","year":"2013","unstructured":"Felipo, V. Hepatic encephalopathy: Effects of liver failure on brain function. Nat. Rev. Neurosci. 14, 851\u2013858 (2013).","journal-title":"Nat. Rev. Neurosci."},{"key":"80941_CR2","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s11011-011-9269-3","volume":"27","author":"V Felipo","year":"2012","unstructured":"Felipo, V. et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab. Brain Dis. 27, 51\u201358 (2012).","journal-title":"Metab. Brain Dis."},{"key":"80941_CR3","doi-asserted-by":"publisher","first-page":"6683","DOI":"10.1038\/s41598-017-05938-1","volume":"7","author":"A Mangas-Losada","year":"2017","unstructured":"Mangas-Losada, A. et al. Minimal hepatic encephalopathy is associated with expansion and activation of CD4+CD28\u2212, Th22 and Tfh and B lymphocytes. Sci. Rep. 7, 6683 (2017).","journal-title":"Sci. Rep."},{"key":"80941_CR4","doi-asserted-by":"publisher","first-page":"3004","DOI":"10.1038\/s41598-018-21399-6","volume":"8","author":"T Balzano","year":"2018","unstructured":"Balzano, T. et al. The cerebellum of patients with steatohepatitis shows lymphocyte infiltration, microglial activation and loss of purkinje and granular neurons. Sci. Rep. 8, 3004 (2018).","journal-title":"Sci. Rep."},{"key":"80941_CR5","doi-asserted-by":"publisher","first-page":"e13270","DOI":"10.1111\/apha.13270","volume":"226","author":"A Cabrera-Pastor","year":"2019","unstructured":"Cabrera-Pastor, A. et al. Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications. Acta Physiol. (Oxf.) 226, e13270 (2019).","journal-title":"Acta Physiol. (Oxf.)"},{"key":"80941_CR6","doi-asserted-by":"publisher","first-page":"4869","DOI":"10.1007\/s00018-019-03255-6","volume":"76","author":"L Fantuzzi","year":"2019","unstructured":"Fantuzzi, L., Tagliamonte, M., Gauzzi, M. C. & Lopalco, L. Dual CCR5\/CCR2 targeting: Opportunities for the cure of complex disorders. Cell Mol. Life Sci. 76, 4869\u20134886 (2019).","journal-title":"Cell Mol. Life Sci."},{"key":"80941_CR7","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1186\/s12879-019-4130-0","volume":"19","author":"L Hu","year":"2019","unstructured":"Hu, L. et al. Potential circulating biomarkers of circulating chemokines CCL5, MIP-1\u03b2 and HA as for early detection of cirrhosis related to chronic HBV (hepatitis B virus) infection. BMC Infect. Dis. 19, 523 (2019).","journal-title":"BMC Infect. Dis."},{"key":"80941_CR8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.neubiorev.2014.02.001","volume":"42","author":"MJ Stuart","year":"2014","unstructured":"Stuart, M. J. & Baune, B. T. Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: A systematic review of biomarker studies. Neurosci. Biobehav. Rev. 42, 93\u2013115 (2014).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"80941_CR9","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1038\/s41597-019-0202-7","volume":"6","author":"D Gomez-Cabrero","year":"2019","unstructured":"Gomez-Cabrero, D. et al. STATegra, a comprehensive multi-omics dataset of B-cell differentiation in mouse. Sci. Data 6, 256 (2019).","journal-title":"Sci. Data"},{"key":"80941_CR10","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa065","author":"X Yu","year":"2020","unstructured":"Yu, X., Lai, S., Chen, H. & Chen, M. Protein\u2013protein interaction network with machine learning models and multi-omics data reveals potential neurodegenerative disease-related proteins. Hum. Mol. Genet. https:\/\/doi.org\/10.1093\/hmg\/ddaa065 (2020).","journal-title":"Hum. Mol. Genet."},{"key":"80941_CR11","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3389\/fgene.2020.00110","volume":"11","author":"MMJ Mens","year":"2020","unstructured":"Mens, M. M. J. et al. Multi-omics analysis reveals microRNAs associated with cardiometabolic traits. Front. Genet. 11, 110 (2020).","journal-title":"Front. Genet."},{"key":"80941_CR12","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/s41398-020-0777-y","volume":"10","author":"H-J Li","year":"2020","unstructured":"Li, H.-J. et al. Further confirmation of netrin 1 receptor (DCC) as a depression risk gene via integrations of multi-omics data. Transl. Psychiatry 10, 98 (2020).","journal-title":"Transl. Psychiatry"},{"key":"80941_CR13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3389\/fnagi.2017.00023","volume":"9","author":"CA Mart\u00edn-Jim\u00e9nez","year":"2017","unstructured":"Mart\u00edn-Jim\u00e9nez, C. A., Salazar-Barreto, D., Barreto, G. E. & Gonz\u00e1lez, J. Genome-scale reconstruction of the human astrocyte metabolic network. Front. Aging Neurosci. 9, 23 (2017).","journal-title":"Front. Aging Neurosci."},{"key":"80941_CR14","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1089\/omi.2018.0088","volume":"22","author":"M Sertbas","year":"2018","unstructured":"Sertbas, M. & Ulgen, K. O. Unlocking human brain metabolism by genome-scale and multiomics metabolic models: Relevance for neurology research, health, and disease. OMICS 22, 455\u2013467 (2018).","journal-title":"OMICS"},{"key":"80941_CR15","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.fob.2014.05.006","volume":"4","author":"M Sertba\u015f","year":"2014","unstructured":"Sertba\u015f, M., Ulgen, K. & Cak\u0131r, T. Systematic analysis of transcription-level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain-specific metabolic network. FEBS Open Bio 4, 542\u2013553 (2014).","journal-title":"FEBS Open Bio"},{"key":"80941_CR16","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1586\/17474124.2016.1141675","volume":"10","author":"M De Rui","year":"2016","unstructured":"De Rui, M., Montagnese, S. & Amodio, P. Recent developments in the diagnosis and treatment of covert\/minimal hepatic encephalopathy. Expert. Rev. Gastroenterol. Hepatol. 10, 443\u2013450 (2016).","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"80941_CR17","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1053\/jhep.2002.31250","volume":"35","author":"P Ferenci","year":"2002","unstructured":"Ferenci, P. et al. Hepatic encephalopathy\u2013definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35, 716\u2013721 (2002).","journal-title":"Hepatology"},{"issue":"Suppl 1","key":"80941_CR18","doi-asserted-by":"publisher","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","volume":"18","author":"W Huber","year":"2002","unstructured":"Huber, W., von Heydebreck, A., S\u00fcltmann, H., Poustka, A. & Vingron, M. Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18(Suppl 1), S96-104 (2002).","journal-title":"Bioinformatics"},{"key":"80941_CR19","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).","journal-title":"Nucleic Acids Res."},{"key":"80941_CR20","doi-asserted-by":"publisher","first-page":"W503","DOI":"10.1093\/nar\/gky466","volume":"46","author":"R Hern\u00e1ndez-de-Diego","year":"2018","unstructured":"Hern\u00e1ndez-de-Diego, R. et al. PaintOmics 3: A web resource for the pathway analysis and visualization of multi-omics data. Nucleic Acids Res. 46, W503\u2013W509 (2018).","journal-title":"Nucleic Acids Res."},{"key":"80941_CR21","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27\u201330 (2000).","journal-title":"Nucleic Acids Res."},{"key":"80941_CR22","doi-asserted-by":"publisher","first-page":"20391","DOI":"10.1038\/srep20391","volume":"6","author":"M Ferrario","year":"2016","unstructured":"Ferrario, M. et al. Mortality prediction in patients with severe septic shock: A pilot study using a target metabolomics approach. Sci. Rep. 6, 20391 (2016).","journal-title":"Sci. Rep."},{"key":"80941_CR23","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ijcme.2016.05.001","volume":"11","author":"K Paapstel","year":"2016","unstructured":"Paapstel, K. et al. Metabolomic profiles of lipid metabolism, arterial stiffness and hemodynamics in male coronary artery disease patients. IJC Metab. Endocr. 11, 13\u201318 (2016).","journal-title":"IJC Metab. Endocr."},{"key":"80941_CR24","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1089\/1536231041388348","volume":"8","author":"PV Purohit","year":"2004","unstructured":"Purohit, P. V., Rocke, D. M., Viant, M. R. & Woodruff, D. L. Discrimination models using variance-stabilizing transformation of metabolomic NMR data. OMICS J. Integr. Biol. 8, 118\u2013130 (2004).","journal-title":"OMICS J. Integr. Biol."},{"key":"80941_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/310372","volume":"2014","author":"R Ibarra","year":"2014","unstructured":"Ibarra, R. et al. Metabolomic analysis of liver tissue from the VX2 rabbit model of secondary liver tumors. HPB Surg. 2014, 1\u201312 (2014).","journal-title":"HPB Surg."},{"key":"80941_CR26","doi-asserted-by":"publisher","first-page":"38881","DOI":"10.1038\/srep38881","volume":"6","author":"B Li","year":"2016","unstructured":"Li, B. et al. Performance evaluation and online realization of data-driven normalization methods used in LC\/MS based untargeted metabolomics analysis. Sci. Rep. 6, 38881 (2016).","journal-title":"Sci. Rep."},{"key":"80941_CR27","doi-asserted-by":"publisher","first-page":"e0203468","DOI":"10.1371\/journal.pone.0203468","volume":"13","author":"CN Ladva","year":"2018","unstructured":"Ladva, C. N. et al. Particulate metal exposures induce plasma metabolome changes in a commuter panel study. PLoS ONE 13, e0203468 (2018).","journal-title":"PLoS ONE"},{"key":"80941_CR28","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.jpba.2017.10.018","volume":"148","author":"H Shin","year":"2018","unstructured":"Shin, H., Medriano, C. A., Park, B., Park, Y. H. & Lee, K. Y. Screening and identification of neuroprotective compounds from Scrophularia buergeriana using cell extraction coupled with LC\u2013MS. J. Pharm. Biomed. Anal. 148, 355\u2013360 (2018).","journal-title":"J. Pharm. Biomed. Anal."},{"key":"80941_CR29","doi-asserted-by":"publisher","first-page":"3092","DOI":"10.1038\/s41467-020-16937-8","volume":"11","author":"S Tarazona","year":"2020","unstructured":"Tarazona, S. et al. Harmonization of quality metrics and power calculation in multi-omic studies. Nat. Commun. 11, 3092 (2020).","journal-title":"Nat. Commun."},{"key":"80941_CR30","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1007\/s10852-005-9022-1","volume":"5","author":"AP Reynolds","year":"2006","unstructured":"Reynolds, A. P., Richards, G., de la Iglesia, B. & Rayward-Smith, V. J. Clustering rules: A comparison of partitioning and hierarchical clustering algorithms. J. Math. Model Algor. 5, 475\u2013504 (2006).","journal-title":"J. Math. Model Algor."},{"key":"80941_CR31","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/0377-0427(87)90125-7","volume":"20","author":"PJ Rousseeuw","year":"1987","unstructured":"Rousseeuw, P. J. Silhouettes: A graphical aid to the interpretation and validation of cluster analysis. J. Comput. Appl. Math. 20, 53\u201365 (1987).","journal-title":"J. Comput. Appl. Math."},{"key":"80941_CR32","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S0169-7439(01)00155-1","volume":"58","author":"S Wold","year":"2001","unstructured":"Wold, S., Sj\u00f6str\u00f6m, M. & Eriksson, L. PLS-regression: A basic tool of chemometrics. Chemometr. Intell. Lab. Syst. 58, 109\u2013130 (2001).","journal-title":"Chemometr. Intell. Lab. Syst."},{"key":"80941_CR33","doi-asserted-by":"publisher","first-page":"e10348","DOI":"10.1371\/journal.pone.0010348","volume":"5","author":"D Montaner","year":"2010","unstructured":"Montaner, D. & Dopazo, J. Multidimensional gene set analysis of genomic data. PLoS ONE 5, e10348 (2010).","journal-title":"PLoS ONE"},{"key":"80941_CR34","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner, M. et al. Gene ontology: Tool for the unification of biology. Nat. Genet. 25, 25\u201329 (2000).","journal-title":"Nat. Genet."},{"key":"80941_CR35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12964-017-0177-y","volume":"15","author":"F Seif","year":"2017","unstructured":"Seif, F. et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun. Signal 15, 23 (2017).","journal-title":"Cell Commun. Signal"},{"key":"80941_CR36","doi-asserted-by":"publisher","first-page":"3823","DOI":"10.1016\/j.molimm.2007.06.151","volume":"44","author":"MJ Glennie","year":"2007","unstructured":"Glennie, M. J., French, R. R., Cragg, M. S. & Taylor, R. P. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol. Immunol. 44, 3823\u20133837 (2007).","journal-title":"Mol. Immunol."},{"key":"80941_CR37","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.4049\/jimmunol.1202098","volume":"191","author":"DED Morsy","year":"2013","unstructured":"Morsy, D. E. D. et al. Reduced T-dependent humoral immunity in CD20-deficient mice. J. Immunol. 191, 3112\u20133118 (2013).","journal-title":"J. Immunol."},{"key":"80941_CR38","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1007\/s002510050517","volume":"49","author":"D McCusker","year":"1999","unstructured":"McCusker, D., Wilson, M. & Trowsdale, J. Organization of the genes encoding the human proteasome activators PA28alpha and beta. Immunogenetics 49, 438\u2013445 (1999).","journal-title":"Immunogenetics"},{"key":"80941_CR39","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/nm1551","volume":"13","author":"L Steinman","year":"2007","unstructured":"Steinman, L. A brief history of T(H)17, the first major revision in the T(H)1\/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139\u2013145 (2007).","journal-title":"Nat. Med."},{"key":"80941_CR40","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1002\/immu.200310023","volume":"33","author":"A Langenkamp","year":"2003","unstructured":"Langenkamp, A. et al. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur. J. Immunol. 33, 474\u2013482 (2003).","journal-title":"Eur. J. Immunol."},{"key":"80941_CR41","doi-asserted-by":"publisher","DOI":"10.1111\/ijlh.13141","author":"S Watanabe","year":"2019","unstructured":"Watanabe, S., Yamada, Y. & Murakami, H. Expression of Th1\/Th2 cell-related chemokine receptors on CD4+ lymphocytes under physiological conditions. Int. J. Lab. Hematol. https:\/\/doi.org\/10.1111\/ijlh.13141 (2019).","journal-title":"Int. J. Lab. Hematol."},{"key":"80941_CR42","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1172\/JCI11902","volume":"107","author":"CH Kim","year":"2001","unstructured":"Kim, C. H. et al. Bonzo\/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J. Clin. Investig. 107, 595\u2013601 (2001).","journal-title":"J. Clin. Investig."},{"key":"80941_CR43","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1084\/jem.187.6.875","volume":"187","author":"F Sallusto","year":"1998","unstructured":"Sallusto, F., Lenig, D., Mackay, C. R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875\u2013883 (1998).","journal-title":"J. Exp. Med."},{"key":"80941_CR44","doi-asserted-by":"publisher","first-page":"547","DOI":"10.4049\/jimmunol.161.2.547","volume":"161","author":"A Zingoni","year":"1998","unstructured":"Zingoni, A. et al. The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells. J. Immunol. 161, 547\u2013551 (1998).","journal-title":"J. Immunol."},{"key":"80941_CR45","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3233\/JAD-2008-14203","volume":"14","author":"M Reale","year":"2008","unstructured":"Reale, M., Iarlori, C., Feliciani, C. & Gambi, D. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer\u2019s disease. J. Alzheimers Dis. 14, 147\u2013159 (2008).","journal-title":"J. Alzheimers Dis."},{"key":"80941_CR46","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.nlm.2009.04.003","volume":"92","author":"YK Lee","year":"2009","unstructured":"Lee, Y. K. et al. CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function. Neurobiol. Learn. Mem. 92, 356\u2013363 (2009).","journal-title":"Neurobiol. Learn. Mem."},{"key":"80941_CR47","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.neurobiolaging.2013.08.001","volume":"35","author":"L Whiley","year":"2014","unstructured":"Whiley, L. et al. Evidence of altered phosphatidylcholine metabolism in Alzheimer\u2019s disease. Neurobiol. Aging 35, 271\u2013278 (2014).","journal-title":"Neurobiol. Aging"},{"key":"80941_CR48","doi-asserted-by":"publisher","first-page":"7713","DOI":"10.1016\/j.chroma.2011.07.073","volume":"1218","author":"MOW Grimm","year":"2011","unstructured":"Grimm, M. O. W. et al. From brain to food: Analysis of phosphatidylcholins, lyso-phosphatidylcholins and phosphatidylcholin-plasmalogens derivates in Alzheimer\u2019s disease human post mortem brains and mice model via mass spectrometry. J. Chromatogr. A 1218, 7713\u20137722 (2011).","journal-title":"J. Chromatogr. A"},{"key":"80941_CR49","doi-asserted-by":"publisher","first-page":"35162","DOI":"10.1074\/jbc.M006403200","volume":"275","author":"SJ Steinberg","year":"2000","unstructured":"Steinberg, S. J., Morgenthaler, J., Heinzer, A. K., Smith, K. D. & Watkins, P. A. Very long-chain acyl-CoA synthetases. Human \u2018bubblegum\u2019 represents a new family of proteins capable of activating very long-chain fatty acids. J. Biol. Chem. 275, 35162\u201335169 (2000).","journal-title":"J. Biol. Chem."},{"key":"80941_CR50","doi-asserted-by":"publisher","first-page":"9912","DOI":"10.1074\/jbc.RA118.001936","volume":"293","author":"R Tidhar","year":"2018","unstructured":"Tidhar, R. et al. Eleven residues determine the acyl chain specificity of ceramide synthases. J. Biol. Chem. 293, 9912\u20139921 (2018).","journal-title":"J. Biol. Chem."},{"key":"80941_CR51","doi-asserted-by":"publisher","first-page":"34414","DOI":"10.1074\/jbc.M113.508812","volume":"288","author":"F Quazi","year":"2013","unstructured":"Quazi, F. & Molday, R. S. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J. Biol. Chem. 288, 34414\u201334426 (2013).","journal-title":"J. Biol. Chem."},{"key":"80941_CR52","doi-asserted-by":"publisher","first-page":"13578","DOI":"10.1074\/jbc.M800008200","volume":"283","author":"J Smith","year":"2008","unstructured":"Smith, J., Su, X., El-Maghrabi, R., Stahl, P. D. & Abumrad, N. A. Opposite regulation of CD36 ubiquitination by fatty acids and insulin: Effects on fatty acid uptake. J. Biol. Chem. 283, 13578\u201313585 (2008).","journal-title":"J. Biol. Chem."},{"key":"80941_CR53","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/ni.2639","volume":"14","author":"FJ Sheedy","year":"2013","unstructured":"Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812\u2013820 (2013).","journal-title":"Nat. Immunol."},{"key":"80941_CR54","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1615\/CritRevImmunol.v37.i2-6.20","volume":"37","author":"M Murakami","year":"2017","unstructured":"Murakami, M., Nakatani, Y., Atsumi, G.-I., Inoue, K. & Kudo, I. Regulatory functions of phospholipase A2. Crit. Rev. Immunol. 37, 121\u2013179 (2017).","journal-title":"Crit. Rev. Immunol."},{"key":"80941_CR55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.6064\/2012\/215308","volume":"2012","author":"CS Hampe","year":"2012","unstructured":"Hampe, C. S. B Cells in autoimmune diseases. Scientifica 2012, 1\u201318 (2012).","journal-title":"Scientifica"},{"key":"80941_CR56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/189096","volume":"2012","author":"MP Pender","year":"2012","unstructured":"Pender, M. P. CD8+ T-cell deficiency, Epstein-Barr virus infection, vitamin D deficiency, and steps to autoimmunity: A unifying hypothesis. Autoimmune Dis. 2012, 1\u201316 (2012).","journal-title":"Autoimmune Dis."},{"key":"80941_CR57","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1177\/1352458514536252","volume":"20","author":"MP Pender","year":"2014","unstructured":"Pender, M. P., Csurhes, P. A., Pfluger, C. M. & Burrows, S. R. Deficiency of CD8 + effector memory T cells is an early and persistent feature of multiple sclerosis. Mult. Scler. 20, 1825\u20131832 (2014).","journal-title":"Mult. Scler."},{"key":"80941_CR58","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1159\/000116820","volume":"32","author":"E Kreuzfelder","year":"1992","unstructured":"Kreuzfelder, E. et al. Enumeration of T, B and natural killer peripheral blood cells of patients with multiple sclerosis and controls. Eur. Neurol. 32, 190\u2013194 (1992).","journal-title":"Eur. Neurol."},{"key":"80941_CR59","doi-asserted-by":"crossref","unstructured":"Zambrano-Zaragoza, J. F., Romo-Mart\u00ednez, E. J., Dur\u00e1n-Avelar, Ma. de J., Garc\u00eda-Magallanes, N. & Vibanco-P\u00e9rez, N. Th17 cells in autoimmune and infectious diseases. Int. J. Inflamm. 2014, 1\u201312 (2014).","DOI":"10.1155\/2014\/651503"},{"key":"80941_CR60","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1096\/fj.201700065R","volume":"31","author":"M Fiala","year":"2017","unstructured":"Fiala, M., Kooij, G., Wagner, K., Hammock, B. & Pellegrini, M. Modulation of innate immunity of patients with Alzheimer\u2019s disease by omega-3 fatty acids. FASEB J. 31, 3229\u20133239 (2017).","journal-title":"FASEB J."},{"key":"80941_CR61","doi-asserted-by":"publisher","first-page":"4359","DOI":"10.1096\/fj.201700290R","volume":"31","author":"HM Olivera-Perez","year":"2017","unstructured":"Olivera-Perez, H. M. et al. Omega-3 fatty acids increase the unfolded protein response and improve amyloid-\u03b2 phagocytosis by macrophages of patients with mild cognitive impairment. FASEB J. 31, 4359\u20134369 (2017).","journal-title":"FASEB J."},{"key":"80941_CR62","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.numecd.2017.07.011","volume":"28","author":"K Paapstel","year":"2018","unstructured":"Paapstel, K. et al. Inverse relations of serum phosphatidylcholines and lysophosphatidylcholines with vascular damage and heart rate in patients with atherosclerosis. Nutr. Metab. Cardiovasc. Dis. 28, 44\u201352 (2018).","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"80941_CR63","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature10449","volume":"478","author":"D Weismann","year":"2011","unstructured":"Weismann, D. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76\u201381 (2011).","journal-title":"Nature"},{"key":"80941_CR64","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nm.3466","volume":"20","author":"M Mapstone","year":"2014","unstructured":"Mapstone, M. et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat. Med. 20, 415\u2013418 (2014).","journal-title":"Nat. Med."},{"key":"80941_CR65","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3390\/ijms20051149","volume":"20","author":"S-H Law","year":"2019","unstructured":"Law, S.-H. et al. An updated review of lysophosphatidylcholine metabolism in human diseases. IJMS 20, 1149 (2019).","journal-title":"IJMS"},{"key":"80941_CR66","doi-asserted-by":"crossref","unstructured":"Mileti\u0107 Vukajlovi\u0107, J. et al. Increased plasma phosphatidylcholine\/lysophosphatidylcholine ratios in patients with Parkinson\u2019s disease. Rapid Commun. Mass Spectrom. 34, (2020).","DOI":"10.1002\/rcm.8595"},{"key":"80941_CR67","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1002\/eji.201545676","volume":"46","author":"S Freigang","year":"2016","unstructured":"Freigang, S. The regulation of inflammation by oxidized phospholipids. Eur. J. Immunol. 46, 1818\u20131825 (2016).","journal-title":"Eur. J. Immunol."},{"key":"80941_CR68","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1089\/ars.2014.6240","volume":"22","author":"C Gimenez-Garz\u00f3","year":"2015","unstructured":"Gimenez-Garz\u00f3, C. et al. Is cognitive impairment in cirrhotic patients due to increased peroxynitrite and oxidative stress?. Antioxid. Redox Signal 22, 871\u2013877 (2015).","journal-title":"Antioxid. Redox Signal"},{"key":"80941_CR69","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.dadm.2015.05.003","volume":"1","author":"K Klavins","year":"2015","unstructured":"Klavins, K. et al. The ratio of phosphatidylcholines to lysophosphatidylcholines in plasma differentiates healthy controls from patients with Alzheimer\u2019s disease and mild cognitive impairment. Alzheimers Dement. (Amst.) 1, 295\u2013302 (2015).","journal-title":"Alzheimers Dement. (Amst.)"},{"key":"80941_CR70","doi-asserted-by":"crossref","unstructured":"Vlasova-St. Louis, I. & Bohjanen, P. R. Post-transcriptional regulation of cytokine and growth factor signaling in cancer. Cytokine Growth Factor Rev. 33, 83\u201393 (2017).","DOI":"10.1016\/j.cytogfr.2016.11.004"},{"key":"80941_CR71","doi-asserted-by":"publisher","first-page":"248","DOI":"10.2183\/pjab.94.017","volume":"94","author":"T Mino","year":"2018","unstructured":"Mino, T. & Takeuchi, O. Post-transcriptional regulation of immune responses by RNA binding proteins. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 94, 248\u2013258 (2018).","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"80941_CR72","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fimmu.2019.00015","volume":"10","author":"V Salvi","year":"2019","unstructured":"Salvi, V., Gianello, V., Tiberio, L., Sozzani, S. & Bosisio, D. Cytokine targeting by miRNAs in autoimmune diseases. Front. Immunol. 10, 15 (2019).","journal-title":"Front. Immunol."},{"key":"80941_CR73","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1111\/j.1365-2249.2004.02586.x","volume":"138","author":"L Golden-Mason","year":"2004","unstructured":"Golden-Mason, L. et al. Hepatic interleuklin 15 (IL-15) expression: Implications for local NK\/NKT cell homeostasis and development. Clin. Exp. Immunol. 138, 94\u2013101 (2004).","journal-title":"Clin. Exp. Immunol."},{"key":"80941_CR74","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1002\/hep.23795","volume":"52","author":"T Aoyama","year":"2010","unstructured":"Aoyama, T., Inokuchi, S., Brenner, D. A. & Seki, E. CX3CL1\u2013CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 52, 1390\u20131400 (2010).","journal-title":"Hepatology"},{"key":"80941_CR75","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1042\/CS20150405","volume":"130","author":"S Rolla","year":"2016","unstructured":"Rolla, S. et al. The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice. Clin. Sci. 130, 193\u2013203 (2016).","journal-title":"Clin. Sci."},{"key":"80941_CR76","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1191\/1352458503ms899oa","volume":"9","author":"DJ Mahad","year":"2003","unstructured":"Mahad, D. J., Lawry, J., Howell, S. J. L. & Woodroofe, M. N. Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse. Mult. Scler. 9, 189\u2013198 (2003).","journal-title":"Mult. Scler."},{"key":"80941_CR77","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1523\/JNEUROSCI.3567-08.2009","volume":"29","author":"C D\u2019Mello","year":"2009","unstructured":"D\u2019Mello, C., Le, T. & Swain, M. G. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J. Neurosci. 29, 2089\u20132102 (2009).","journal-title":"J. Neurosci."},{"issue":"Pt 9","key":"80941_CR78","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1093\/brain\/123.9.1874","volume":"123","author":"YC Zang","year":"2000","unstructured":"Zang, Y. C. et al. Aberrant T cell migration toward RANTES and MIP-1 alpha in patients with multiple sclerosis. Overexpression of chemokine receptor CCR5. Brain 123(Pt 9), 1874\u20131882 (2000).","journal-title":"Brain"},{"key":"80941_CR79","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.4049\/jimmunol.1300758","volume":"192","author":"X Pei","year":"2014","unstructured":"Pei, X. et al. PC3-secreted microprotein is a novel chemoattractant protein and functions as a high-affinity ligand for CC chemokine receptor 2. J. Immunol. 192, 1878\u20131886 (2014).","journal-title":"J. Immunol."},{"key":"80941_CR80","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1084\/jem.20041310","volume":"201","author":"W Vermi","year":"2005","unstructured":"Vermi, W. et al. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J. Exp. Med. 201, 509\u2013515 (2005).","journal-title":"J. Exp. Med."},{"key":"80941_CR81","doi-asserted-by":"publisher","first-page":"11815","DOI":"10.3748\/wjg.v21.i41.11815","volume":"21","author":"M Luo","year":"2015","unstructured":"Luo, M. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis. WJG 21, 11815 (2015).","journal-title":"WJG"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80941-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80941-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80941-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T05:07:08Z","timestamp":1674882428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80941-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,21]]},"references-count":81,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["80941"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-80941-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,21]]},"assertion":[{"value":"8 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1907"}}