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

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/ß-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.

Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo.

ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12-/- mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12-/- mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12-/- mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo.

FAAH, but not MAGL, inhibition modulates acute TLR3-induced neuroimmune signaling in the rat, independent of sex.

Toll-like receptor (TLR)3 is a key component of the innate immune response to viral infection. The present study firstly examined whether sex differences exist in TLR3-induced inflammatory, endocrine, and sickness responses. The data revealed that TLR3-induced expression of interferon- or NFkB-inducible genes (IFN-α/ß, IP-10, or TNF-α), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3-induced IFN-α expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight - effects independent of sex. Thus, the acute-phase inflammatory, endocrine, and sickness responses to TLR3 activation exhibit minimal sex-related differences. A further aim of this study was to examine whether enhancing endocannabinoid tone - namely, 2-arachidonylglycerol (2-AG) or N-arachidonoylethanolamine (AEA), exhibited similar effects on TLR3-induced inflammatory responses in male versus female rats. Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2-AG levels did not alter the TLR3-induced increase in IP-10, IRF7, or TNF-α expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N-acylethanolamines, an effect associated with the attenuation of TLR3-induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats. These data support a role for FAAH, but not MAGL, substrates in the modulation of TLR3-induced neuroinflammatory responses, effects independent of sex.

Selective axonal and glial distribution of monoacylglycerol lipase immunoreactivity in the superficial spinal dorsal horn of rodents.

The importance of 2-AG-mediated endogenous cannabinoid signaling in spinal pain control has recently been well substantiated. Although the degradation of 2-AG seems to be essential in cannabinoid-mediated spinal nociceptive information processing, no experimental data are available about the cellular distribution of monoacylglycerol lipase (MGL), the main degrading enzyme of 2-AG in the spinal dorsal horn. Thus, here we investigated the cellular distribution of MGL in laminae I-II of the spinal gray matter with immunocytochemical methods and revealed an abundant immunoreactivity for MGL in the rodent superficial spinal dorsal horn. We addressed the co-localization of MGL with markers of peptidergic and non-peptidergic primary afferents, axon terminals of putative glutamatergic and GABAergic spinal neurons, as well as astrocytic and microglial profiles, and we found that nearly 17 % of the peptidergic (immunoreactive for CGRP), a bit more than 10 % of the axon terminals of putative glutamatergic spinal neurons (immunoreactive for VGLUT2), and approximately 20 % of the astrocytic (immunoreactive for GFAP) profiles were immunolabeled for MGL. On the other hand, however, axon terminals of non-peptidergic (binding isolectin-B4) nociceptive primary afferents and putative inhibitory spinal neurons (immunoreactive for VGAT) as well as microglial (immunoreactive for CD11b) profiles showed negligible immunostaining for MGL. The results suggest that only nociceptive inputs arriving through a population of CGRP immunoreactive fibers are modulated by the spinal DGLα-MGL pathway. We also postulate that the DGLα-MGL signaling pathway may modulate spinal excitatory but not inhibitory neural circuits.