{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:26:57Z","timestamp":1790414817590,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) \u03b6, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgk\u03b6 deficiency results in reduced production of TNF-\u03b1, IL-6, and IL-1\u03b2 and in limited M1 macrophage polarization. Mechanistically, Dgk\u03b6 deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgk\u03b6 levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgk\u03b6 induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgk\u03b6\u2013DAG\/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.<\/jats:p>","DOI":"10.4049\/jimmunol.1900721","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T16:35:57Z","timestamp":1575477357000},"page":"137-146","source":"Crossref","is-referenced-by-count":18,"title":["Diacylglycerol Kinase \u03b6 Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models"],"prefix":"10.1093","volume":"204","author":[{"given":"Sahil","family":"Mahajan","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2577-139X","authenticated-orcid":false,"given":"Elizabeth D","family":"Mellins","sequence":"additional","affiliation":[{"name":"Program in Immunology and Allergy, Department of Pediatrics, Stanford University , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Faccio","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine , St. Louis, MO 63110"},{"name":"Shriners Hospitals for Children , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2025030417510193300_r1","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.clim.2015.04.018","article-title":"Current understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches","volume":"159","author":"Bruck","year":"2015","journal-title":"Clin. Immunol."},{"key":"2025030417510193300_r2","first-page":"390","article-title":"International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001","volume":"31","author":"Petty","year":"2004","journal-title":"J. Rheumatol."},{"key":"2025030417510193300_r3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1136\/adc.85.5.421","article-title":"Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders","volume":"85","author":"Sawhney","year":"2001","journal-title":"Arch. Dis. Child."},{"key":"2025030417510193300_r4","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/S0022-3476(96)70140-3","article-title":"Macrophage activation syndrome in systemic juvenile rheumatoid arthritis","volume":"129","author":"Grom","year":"1996","journal-title":"J. Pediatr."},{"key":"2025030417510193300_r5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.2147\/OARRR.S151013","article-title":"Macrophage activation syndrome: early diagnosis is key","volume":"10","author":"Lerkvaleekul","year":"2018","journal-title":"Open Access Rheumatol."},{"key":"2025030417510193300_r6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.berh.2014.03.002","article-title":"Macrophage activation syndrome and cytokine-directed therapies","volume":"28","author":"Schulert","year":"2014","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"2025030417510193300_r7","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1182\/blood-2003-10-3413","article-title":"An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder","volume":"104","author":"Jordan","year":"2004","journal-title":"Blood"},{"key":"2025030417510193300_r8","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev-med-041610-134208","article-title":"Familial and acquired hemophagocytic lymphohistiocytosis","volume":"63","author":"Janka","year":"2012","journal-title":"Annu. Rev. Med."},{"key":"2025030417510193300_r9","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1182\/blood-2015-12-684399","article-title":"Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis","volume":"127","author":"Das","year":"2016","journal-title":"Blood"},{"key":"2025030417510193300_r10","doi-asserted-by":"crossref","first-page":"10944","DOI":"10.1073\/pnas.1524487113","article-title":"TLR9-mediated inflammation drives a Ccr2-independent peripheral monocytosis through enhanced extramedullary monocytopoiesis","volume":"113","author":"Weaver","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417510193300_r11","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1055\/s-0043-106445","article-title":"[Hepatic manifestation of a macrophage activation syndrome (MAS)]","volume":"55","author":"Nagel","year":"2017","journal-title":"Z. Gastroenterol."},{"key":"2025030417510193300_r12","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1182\/blood-2004-08-2997","article-title":"Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages","volume":"105","author":"Billiau","year":"2005","journal-title":"Blood"},{"key":"2025030417510193300_r13","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/ng.3089","article-title":"An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome","volume":"46","author":"Canna","year":"2014","journal-title":"Nat. Genet."},{"key":"2025030417510193300_r14","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1002\/art.22981","article-title":"Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome","volume":"56","author":"Fall","year":"2007","journal-title":"Arthritis Rheum."},{"key":"2025030417510193300_r15","doi-asserted-by":"crossref","first-page":"769","DOI":"10.3899\/jrheum.100655","article-title":"Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis","volume":"38","author":"Yanagimachi","year":"2011","journal-title":"J. Rheumatol."},{"key":"2025030417510193300_r16","doi-asserted-by":"crossref","DOI":"10.1126\/science.aao5213","article-title":"Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes","volume":"363","author":"Akilesh","year":"2019","journal-title":"Science"},{"key":"2025030417510193300_r17","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jaut.2019.02.005","article-title":"Plc\u03b32\/Tmem178 dependent pathway in myeloid cells modulates the pathogenesis of cytokine storm syndrome","volume":"100","author":"Mahajan","year":"2019","journal-title":"J. Autoimmun."},{"key":"2025030417510193300_r18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.coi.2010.11.006","article-title":"Nucleic acid sensing toll-like receptors in autoimmunity","volume":"23","author":"Ewald","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"2025030417510193300_r19","article-title":"The role of toll-like receptors in autoimmune diseases through failure of the self-recognition mechanism","volume":"2017","author":"Farrugia","year":"2017","journal-title":"Int. J. Inflamm."},{"key":"2025030417510193300_r20","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0968-0004(98)01200-6","article-title":"Diacylglycerols and phosphatidates: which molecular species are intracellular messengers?","volume":"23","author":"Hodgkin","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"2025030417510193300_r21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0962-8924(94)90145-7","article-title":"First thoughts on lipid second messengers","volume":"4","author":"Roberts","year":"1994","journal-title":"Trends Cell Biol."},{"key":"2025030417510193300_r22","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S1567-5769(01)00069-8","article-title":"Phosphatidylcholine-specific phospholipase C and D in stimulation of RAW264.7 mouse macrophage-like cells by lipopolysaccharide","volume":"1","author":"Zhang","year":"2001","journal-title":"Int. Immunopharmacol."},{"key":"2025030417510193300_r23","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.4049\/jimmunol.162.5.3005","article-title":"A phosphatidylcholine-specific phospholipase C regulates activation of p42\/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages","volume":"162","author":"Monick","year":"1999","journal-title":"J. Immunol."},{"key":"2025030417510193300_r24","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.bbalip.2007.04.006","article-title":"Diacylglycerol kinases: why so many of them?","volume":"1771","author":"Sakane","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030417510193300_r25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20071040","article-title":"Diacylglycerol kinases: at the hub of cell signalling","volume":"409","author":"M\u00e9rida","year":"2008","journal-title":"Biochem. J."},{"key":"2025030417510193300_r26","doi-asserted-by":"crossref","first-page":"6186","DOI":"10.1021\/cr1004106","article-title":"Regulation and functions of diacylglycerol kinases","volume":"111","author":"Shulga","year":"2011","journal-title":"Chem. Rev."},{"key":"2025030417510193300_r27","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1002\/jbmr.2533","article-title":"Diacylglycerol kinase \u03b6 (DGK\u03b6) is a critical regulator of bone homeostasis via modulation of c-Fos levels in osteoclasts","volume":"30","author":"Zamani","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"2025030417510193300_r28","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1084\/jem.20061856","article-title":"Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii","volume":"204","author":"Liu","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030417510193300_r29","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1038\/ni958","article-title":"Enhanced T cell responses due to diacylglycerol kinase zeta deficiency","volume":"4","author":"Zhong","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025030417510193300_r30","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1359\/jbmr.2000.15.8.1477","article-title":"Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts","volume":"15","author":"Takeshita","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"2025030417510193300_r31","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1172\/JCI43157","article-title":"Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice","volume":"121","author":"Behrens","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2025030417510193300_r32","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S1471-4906(03)00139-X","article-title":"PI3K and negative regulation of TLR signaling","volume":"24","author":"Fukao","year":"2003","journal-title":"Trends Immunol."},{"key":"2025030417510193300_r33","doi-asserted-by":"crossref","first-page":"236","DOI":"10.4049\/jimmunol.179.1.236","article-title":"Role of phosphatidylinositol-3 kinase in transcriptional regulation of TLR-induced IL-12 and IL-10 by Fc gamma receptor ligation in murine macrophages","volume":"179","author":"Polumuri","year":"2007","journal-title":"J. Immunol."},{"key":"2025030417510193300_r34","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"2025030417510193300_r35","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1146\/annurev-physiol-022516-034339","article-title":"Macrophage polarization","volume":"79","author":"Murray","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"2025030417510193300_r36","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.celrep.2014.09.032","article-title":"Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice","volume":"9","author":"Misharin","year":"2014","journal-title":"Cell Rep."},{"key":"2025030417510193300_r37","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.clim.2011.12.008","article-title":"Alternative activation in systemic juvenile idiopathic arthritis monocytes","volume":"142","author":"Macaubas","year":"2012","journal-title":"Clin. Immunol."},{"key":"2025030417510193300_r38","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.immuni.2017.07.014","article-title":"Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. [Published erratum appears in 2017 Immunity 47: 597.]","volume":"47","author":"Zhu","year":"2017","journal-title":"Immunity"},{"key":"2025030417510193300_r39","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.cell.2018.09.030","article-title":"High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. [Published erratum appears in 2018 Cell 175: 1443.]","volume":"175","author":"Gubin","year":"2018","journal-title":"Cell"},{"key":"2025030417510193300_r40","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aau8587","article-title":"HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness","volume":"11","author":"Kuo","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"2025030417510193300_r41","doi-asserted-by":"crossref","first-page":"747","DOI":"10.14348\/molcells.2014.0220","article-title":"PKC\u03b2 positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3\u03b2","volume":"37","author":"Shin","year":"2014","journal-title":"Mol. Cells"},{"key":"2025030417510193300_r42","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S8756-3282(02)00976-6","article-title":"Participation of protein kinase C beta in osteoclast differentiation and function","volume":"32","author":"Lee","year":"2003","journal-title":"Bone"},{"key":"2025030417510193300_r43","doi-asserted-by":"crossref","first-page":"45117","DOI":"10.1074\/jbc.M303789200","article-title":"Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway","volume":"278","author":"Lim","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2025030417510193300_r44","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/jlb.41.5.450","article-title":"Zymosan-stimulated production of phosphatidic acid by macrophages: relationship to release of superoxide anion and inhibition by agents that increase intracellular cyclic AMP","volume":"41","author":"Channon","year":"1987","journal-title":"J. Leukoc. Biol."},{"key":"2025030417510193300_r45","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ni1400","article-title":"Disruption of diacylglycerol metabolism impairs the induction of T cell anergy","volume":"7","author":"Olenchock","year":"2006","journal-title":"Nat. Immunol."},{"key":"2025030417510193300_r46","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1084\/jem.20052424","article-title":"Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells","volume":"203","author":"Olenchock","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030417510193300_r47","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1002\/art.23757","article-title":"Vav\/phospholipase Cgamma2-mediated control of a neutrophil-dependent murine model of rheumatoid arthritis","volume":"58","author":"Cremasco","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025030417510193300_r48","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jaut.2019.04.015","article-title":"Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1","volume":"101","author":"Yang","year":"2019","journal-title":"J. Autoimmun."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/1\/137\/61358863\/ji1900721.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/1\/137\/61358863\/ji1900721.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T13:25:20Z","timestamp":1741094720000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/204\/1\/137\/7943751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1900721","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,1]]},"published":{"date-parts":[[2020,1,1]]}}}