No abstract

Dexmedetomidine reduced mortality rate and had an inhibitory effect on inflammatory response during endotoxemia. These findings suggest that dexmedetomidine administration may inhibit the inflammatory response.

Summary Lipid metabolism has emerged as an important modulator of innate and adaptive immune cell fate and function. The lipid-activated transcription factors PPAR (PPARα, β/δ, γ) and LXR are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. Accumulated evidence over the last decade indicates that PPAR and LXR signaling also influences multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Herein, we provide a brief introduction to LXR and PPAR biology and review recent discoveries highlighting the importance of PPAR and LXR signaling in the modulation of normal and pathologic states of immunity. We also examine advances in our mechanistic understanding of how nuclear receptors impact immune system function and homeostasis. Finally, we discuss whether LXRs and PPARs could be pharmacologically manipulated to provide novel therapeutic approaches for modulation of the immune system under pathologic inflammation or in the context of allergic and autoimmune disease.

SREBPs are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of Fatty Acid Synthase activity from SCD1-mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism.

The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 10 9 neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop have remained indeterminate. Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate both lipid metabolic and inflammatory gene expression. Here, we demonstrate that LXRs contribute to the control of neutrophil homeostasis. Using gain-and lossof-function models, we found that LXR signaling regulated the efficient clearance of senescent neutrophils by peripheral tissue APCs in a Mer-dependent manner. Furthermore, activation of LXR by engulfed neutrophils directly repressed the IL-23/IL-17/G-CSF granulopoietic cytokine cascade. These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression.

During persistent viral infection, adaptive immune responses are suppressed by immunoregulatory factors, contributing to viral persistence. Although this suppression is mediated by inhibitory factors, the mechanisms by which virus-specific T cells encounter and integrate immunoregulatory signals during persistent infection are unclear. We show that a distinct population of IL-10-expressing immunoregulatory antigen presenting cells (APC) is amplified during chronic versus acute lymphocytic choriomeningitis virus (LCMV) infection and suppresses T cell responses. Although acute LCMV infection induces the expansion of immunoregulatory APC, they subsequently decline. However, during persistent LCMV infection, immunoregulatory APC are amplified and parallel the viral replication kinetics. Further characterization demonstrates that immunoregulatory APC are molecularly and metabolically distinct, and exhibit increased expression of T cell-interacting molecules and negative regulatory factors that suppress T cell responses. Thus, immunoregulatory APC are amplified during viral persistence and deliver inhibitory signals that suppress antiviral T cell immunity and likely contribute to persistent infection.

The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness.Clinicaltrials.gov NCT01582737.Electronic supplementary materialThe online version of this article (10.1007/s11239-019-01934-6) contains supplementary material, which is available to authorized users.

In our previous study, ketamine administration was found to inhibit hypotension, metabolic acidosis, and cytokine responses in endotoxemia. However, only a few studies have indicated whether ketamine has the dose-related beneficial effects after endotoxin injection. Our objective was to clarify the dose-related effects of ketamine on mortality and cytokine responses to endotoxemia in rats. Sixty-five rats were divided at random among five equal groups: Group C was given saline alone. Group E was given endotoxin alone (Escherichia coli endotoxin; 10 mg/kg, IV). Group L received a a low dose of ketamine (5 mg.kg(-1).h(-1), IV), Group M a medium dose of ketamine (10 mg.kg(-1).h(-1), IV), and Group H a high dose of ketamine (20 mg.kg(-1).h(-1), IV), all exposure to endotoxin. After endotoxin injection, hemodynamics, acid-base status, mortality rate, and plasma concentrations of tumor necrosis factor alpha and interleukin 6 were assessed for each of the five groups. Endotoxin injection produced progressive hypotension, metabolic acidosis, and a large increase in plasma cytokine concentrations. Mortality rates 8 h after endotoxin injection were 0% for group C, 92% for group E, 48% for group L, 0% for group M, and 32% for group H. Ketamine administration thus clearly had a beneficial effect on mortality rates, with that for group M lower than for groups L and H (P < 0.05). The cytokine responses to endotoxin were somewhat suppressed in group M but not in group L. Ketamine administration dose-independently inhibited hypotension, metabolic acidosis, and cytokine responses in rats injected with endotoxin.