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Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis
Author(s) -
Chiurchiù Valerio,
Cencioni Maria Teresa,
Bisicchia Elisa,
Bardi Marco,
Gasperini Claudio,
Borsellino Giovanna,
Centonze Diego,
Battistini Luca,
Maccarrone Mauro
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23875
Subject(s) - anandamide , endocannabinoid system , cytokine , immunology , myeloid , chemokine , multiple sclerosis , fatty acid amide hydrolase , cannabinoid receptor , biology , immune system , receptor , biochemistry , agonist
Objective The immunopathogenesis of multiple sclerosis (MS) has always been thought to be driven by chronically activated and autoreactive Th‐1 and Th‐17 cells. Recently, dendritic cells (DCs) have also been thought to significantly contribute to antigenic spread and to maturation of adaptive immunity, and have been linked with disease progression and exacerbation. However, the role of DCs in MS pathogenesis remains poorly understood. Methods We compared the level of cytokine production by myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in healthy subjects and MS patients, following in vitro stimulation of Toll‐like receptors 7/8. We also evaluated the effect of the main endocannabinoid, anandamide (AEA), in these DC subsets and correlated cytokine levels with defects in the endocannabinoid system. Results mDCs obtained from MS patients produce higher levels of interleukin‐12 and interleukin‐6, whereas pDCs account for lower levels of interferon‐α compared to healthy subjects. AEA significantly inhibited cytokine production from healthy mDCs and pDCs, as well as their ability to induce Th‐1 and Th‐17 lineages. Moreover, we found that in MS only pDCs lack responsiveness to cytokine inhibition induced by AEA. Consistently, this specific cell subset expresses higher levels of the anandamide hydrolase fatty acid amide hydrolase (FAAH). Interpretation Our data disclose a distinct immunomodulatory effect of AEA in mDCs and pDCs from MS patients, which may reflect an alteration of the expression of FAAH, thus forming the basis for the rational design of new endocannabinoid‐based immunotherapeutic agents targeting a specific cell subset. Ann Neurol 2013;73:626–636