Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases

GM-CSF Signalling Boosts Dramatically IL-1Production

GM-CSF is mostly known for its capacity to promote bone marrow progenitor differentiation, to mobilize and mature myeloid cells as well as to enhance host immune responses. However the molecular actions of GM-CSF are still poorly characterized. Here we describe a new surprising facet of this “old” growth factor as a key regulator involved in IL-1βsecretion. We found that IL-1β release, a pivotal component of the triggered innate system, is heavily dependent on the signaling induced by GM-CSF in such an extent that in its absence IL-1β is only weakly secreted. GM-CSF synergizes with LPS for IL-1β secretion mainly at the level of pro-IL-1β production via strengthening the NF-κB signaling. In addition, we show that expression of Rab39a, a GTPase required for caspase-1 dependent IL-1β secretion is greatly augmented by LPS and GM-CSF co-stimulation suggesting a potential GM-CSF contribution in enhancing IL-1β exocytosis. The role of GM-CSF in regulating IL-1β secretion is extended also in vivo, since GM-CSF R−/− mice are more resistant to LPS-mediated septic shock. These results identify GM-CSF as a key regulator of IL-1β production and indicate GM-CSF as a previously underestimated target for therapeutic intervention

Sperm Mitochondrial DNA Copy Number Is Not a Predictor of Intracytoplasmic Sperm Injection (ICSI) Cycle Outcomes

This study is to determine if sperm mitochondrial DNA copy number (mtDNA CN) is associated with fertilization, blastulation, blastocyst euploidy, and live birth rates in in vitro fertilization (IVF) with ICSI cycles. This is a cohort study conducted on stored sperm samples which were collected prospectively and used to create blastocysts transferred in a couple's first ICSI transfer cycle between 2007 and 2013 at a single large infertility center. Samples from ICSI cycles utilizing surgical or cryopreserved sperm or day 3 embryo biopsy were excluded. The primary outcome was live birth rate. Secondary outcomes included fertilization, usable blastocyst development, and blastocyst euploidy rates. Unique sperm samples used to create transferred embryos were identified. Mitochondrial DNA CN was evaluated using TaqMan® quantitative real-time polymerase chain reaction (qPCR) assays normalized to a nuclear control for relative quantitation. Linear regression and mixed effects logistic regression used were appropriate. A total of 2062 unique sperm samples used to create transferred embryos were included. Lower relative sperm mtDNA content was associated with increased pre-wash sperm motility (p < 0.001). No significant association was identified between sperm mtDNA CN and fertilization (p = 0.40), usable blastocyst development (p = 0.36), blastocyst euploid (p = 0.10), and live birth rates (p = 0.42) while adjusting for sperm pre-wash motility and maternal age. Sperm mtDNA CN is not prognostic of fertilization, usable blastocyst development, euploidy and live birth rates in an infertile population undergoing IVF with ICSI