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J Immunol. 2019 Feb 6. pii: ji1801521. doi: 10.4049/jimmunol.1801521. [Epub ahead of print]

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype.

Author information

1
Indian Institute of Chemical Biology-Translational Research Unit of Excellence, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, West Bengal 700091, India.
2
Division of Cancer Biology and Inflammatory Disorders, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, West Bengal 700091, India.
3
Mass Spectrometry Core Facility, Indian Institute of Chemical Biology-Translational Research Unit of Excellence, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, West Bengal 700091, India; and.
4
Department of Rheumatology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal 700020, India.
5
Indian Institute of Chemical Biology-Translational Research Unit of Excellence, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, West Bengal 700091, India; dipyaman@iicb.res.in.

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, characterized by loss of tolerance toward self nuclear Ags. Systemic induction of type I IFNs plays a pivotal role in SLE, a major source of type I IFNs being the plasmacytoid dendritic cells (pDCs). Several genes have been linked with susceptibility to SLE in genome-wide association studies. We aimed at exploring the role of one such gene, α/β-hydrolase domain-containing 6 (ABHD6), in regulation of IFN-α induction in SLE patients. We discovered a regulatory role of ABHD6 in human pDCs through modulating the local abundance of its substrate, the endocannabinoid 2-arachidonyl glycerol (2-AG), and elucidated a hitherto unknown cannabinoid receptor 2 (CB2)-mediated regulatory role of 2-AG on IFN-α induction by pDCs. We also identified an ABHD6High SLE endophenotype wherein reduced local abundance of 2-AG relieves the CB2-mediated steady-state resistive tuning on IFN-α induction by pDCs, thereby contributing to SLE pathogenesis.

PMID:
30728209
DOI:
10.4049/jimmunol.1801521

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