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Cutting Edge: Dysregulated Endocannabinoid-Rheostat For Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype This information is current as of September 23, 2021. Oindrila Rahaman, Roopkatha Bhattacharya, Chinky Shiu Chen Liu, Deblina Raychaudhuri, Amrit Raj Ghosh, Purbita Bandopadhyay, Santu Pal, Rudra Prasad Goswami, Geetabali Sircar, Parasar Ghosh and Dipyaman Ganguly J Immunol published online 6 February 2019 Downloaded from http://www.jimmunol.org/content/early/2019/02/05/jimmun ol.1801521 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2019/02/05/jimmunol.180152 Material 1.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 23, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 6, 2019, doi:10.4049/jimmunol.1801521 Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype Oindrila Rahaman,*,† Roopkatha Bhattacharya,*,† Chinky Shiu Chen Liu,*,† ,† ,† ,† Deblina Raychaudhuri,* Amrit Raj Ghosh,*x Purbitax Bandopadhyay,* x Santu Pal,*,‡ Rudra Prasad Goswami, Geetabali Sircar, Parasar Ghosh, and Dipyaman Ganguly*,† Systemic lupus erythematosus (SLE) is a systemic auto- produced by the plasmacytoid dendritic cells (pDCs) have immune disease, characterized by loss of tolerance to- been found to be a crucial event in SLE pathogenesis (3, 4). ward self nuclear Ags. Systemic induction of type I Genome-wide association studies have linked multiple genomic Downloaded from IFNs plays a pivotal role in SLE, a major source of type loci with SLE susceptibility, although direct pathogenetic role I IFNs being the plasmacytoid dendritic cells (pDCs). of very few of them have been reported, apart from the genes Several genes have been linked with susceptibility to directly linked to induction and response of type I IFNs (5, 6). SLE in genome-wide association studies. We aimed A recent genome-wide association study had reported associa- at exploring the role of one such gene, a/b-hydrolase tion of a novel gene, a/b-hydrolase domain-containing 6 domain-containing 6 (ABHD6), in regulation of IFN-a (ABHD6), with SLE susceptibility (7). http://www.jimmunol.org/ induction in SLE patients. We discovered a regulatory ABHD6 is a serine hydrolase that catalyzes hydrolysis of role of ABHD6 in human pDCs through modulating endocannabinoids, the endogenous ligands for the G-protein– the local abundance of its substrate, the endocannabinoid coupled cannabinoid receptors (CB1 and CB2), which include 2-arachidonyl glycerol (2-AG), and elucidated a hitherto 2-arachidonyl glycerol (2-AG) and anandamide (AEA) (8). The unknown cannabinoid receptor 2 (CB2)–mediated reg- role of ABHD6, as the major hydrolytic enzyme for 2-AG, was ulatory role of 2-AG on IFN-a induction by pDCs. first documented in microglia cells in the CNS (9). Expression We also identified an ABHD6High SLE endophenotype of ABHD6 with a similar function in macrophages was by guest on September 23, 2021 wherein reduced local abundance of 2-AG relieves the also reported (10). In macrophages, ABHD6-mediated hy- CB2-mediated steady-state resistive tuning on IFN-a drolysis of 2-AG prevented 2-AG–driven inhibition of induction by pDCs, thereby contributing to SLE TLR activation; thus, ABHD6 activity was found to have a pathogenesis. The Journal of Immunology, 2019, 202: proinflammatory role. Systemic immunomodulatory role of 000–000. cannabinoid receptor signaling is widely reported, and a link with autoreactive inflammation is also suggested (11). Apart from modulation of endocannabinoids, the substrate of ystemic autoimmunity in systemic lupus erythematosus ABHD6, function of this enzyme is also reported in various (SLE) is characterized by humoral autoreactivity against other physiological contexts, namely receptor recycling in the S nuclear Ags and immune-complex deposition leading to CNS (12), insulin secretion by pancreatic b cells (13), and pathologies involving multiple organs, namely skin, joints, lipolysis in metabolic tissues (14). Accordingly, deregulation vessels, CNS, and kidneys (1). Due to complex genetic factors of this enzyme has been implicated in various clinical contexts associated with the disease and a dominant systemic type I IFN of CNS disorders and metabolic disorders (13–15), but any response critically linked to the pathogenesis, SLE is a proto- pathogenetic role of ABHD6 in immunological disorders typical member of polygenic IFNopathies (2). Type I IFNs remains unidentified. In this study, we aimed at exploring *Indian Institute of Chemical Biology–Translational Research Unit of Excellence, Coun- University Grants Commission, India. R.B., C.S.C.L., D.R., and P.B. received fellow- cil of Scientific and Industrial Research–Indian Institute of Chemical Biology, Kolkata, ships from the Council of Scientific and Industrial Research, India. West Bengal 700091, India; †Division of Cancer Biology and Inflammatory Disorders, Address correspondence and reprint requests to Dr. Dipyaman Ganguly, Indian Institute Council of Scientific and Industrial Research–Indian Institute of Chemical Biology, ‡ of Chemical Biology –Translational Research Unit of Excellence, Council of Scientific Kolkata, West Bengal 700091, India; Mass Spectrometry Core Facility, Indian Institute and Industrial Research–Indian Institute of Chemical Biology, CN6, Sector V, Salt of Chemical Biology–Translational Research Unit of Excellence, Council of Scientific Lake, Kolkata, West Bengal 700091, India. E-mail address: [email protected] and Industrial Research–Indian Institute of Chemical Biology, Kolkata, West Bengal x 700091, India; and Department of Rheumatology, Institute of Postgraduate Medical The online version of this article contains supplemental material. Education and Research, Kolkata, West Bengal 700020, India Abbreviations used in this article: ABHD6, a/b-hydrolase domain-containing 6; 2-AG, ORCID: 0000-0002-7786-1795 (D.G.). 2-arachidonyl glycerol; COX2, cycloxygenase-2; ISG, IFN signature gene; pDC, plas- macytoid dendritic cell; PPARa, proliferator-activated receptor a; siRNA, small inter- Received for publication November 19, 2018. Accepted for publication January 20, fering RNA; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index. 2019. This work was supported by a Ramanujan Fellowship from the Science and Engineer- Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 ing Research Board, India (to D.G.). O.R. and A.R.G. received fellowships from the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801521 2 CUTTING EDGE: ENDOCANNABINOID CONTROL OF PLASMACYTOID DCs IN SLE functional link of this gene with type I IFN induction and spectrometry of 2-AG on LTQ Orbitrap XL. The output was analyzed by SLE pathogenesis. Thermo Xcalibur software. Materials and Methods ELISA Blood sample collection from healthy donors and SLE patients ELISA was done to quantify IFN-a and TNF-a from PBMC and pDC culture supernatants, using anti-human IFN-a ELISA kit and anti-human Healthy individuals (n = 76) and SLE patients (n = 90) were recruited for the TNF-a ELISA kit (Mabtech). study; patients were recruited at the Department of Rheumatology at the Institute of Postgraduate Medical Education and Research, Kolkata, India Statistics (Supplemental Fig. 1A, 1B). Peripheral blood samples were collected from SLE patients and healthy donors, after taking written informed consent, in Statistical analyses of all data sets were done on GraphPad Prism 5.0 software. accordance with the Declaration of Helsinki and as recommended and ap- Data were compared between groups using paired, unpaired Student t test or proved by the institutional review boards of both the institutes (Institute of Mann–Whitney U test as specified in figure legends, and correlations were Postgraduate Medical Education and Research and Council of Scientific and done using Spearman rank correlation as specified in respective figure legends. Industrial Research–Indian Institute of Chemical Biology, Kolkata, India). Cell isolation and culture Results and Discussion PBMCs were isolated from whole blood. PBMCs were either kept in TRIzol Higher expression of ABHD6 in PBMCs defines an reagent for subsequent RNA isolation or cultured overnight in RPMI 1640 SLE endophenotype with 10% FBS in a 96-well plate at a density of 0.2 million cells per well and were treated with agonists and/or inhibitors as indicated. Collected plasma An overexpression of ABHD6 in SLE patients was suggested in was stored at 280˚C for future use. In some cases, pDCs were isolated from Downloaded from PBMCs by magnetic immunoselection using BDCA-4 MicroBeads (Miltenyi the previous study, which first identified polymorphisms of Biotec) and
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