Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease

Quantitative Prediction and Clinical Observation of a CYP3A Inhibitor-Based Drug-Drug Interactions with MLN3897, a Potent C-C Chemokine Receptor-1 Antagonist

ABSTRACT A novel in vitro model was recently developed in our laboratories for the prediction of magnitude of clinical pharmacokinetic drugdrug interactions (DDIs), based on reversible hepatic cytochrome P450 (P450) inhibition. This approach, using inhibition data from human hepatocytes incubated in human plasma, and quantitative P450 phenotyping data from hepatic microsomal incubations, successfully predicted DDIs for 15 marketed drugs with ketoconazole, a strong competitive inhibitor of CYP3A4/5, generally used to demonstrate a "worst-case scenario" for CYP3A inhibition. In addition, this approach was successfully extended to DDI predictions with the moderate competitive CYP3A inhibitor fluconazole for nine marketed drugs. In the current report, the general applicability of the model has been demonstrated by prospectively predicting the degree of inhibition and then conducting DDI studies in the clinic for an investigational CCR1 antagonist MLN3897, which is cleared predominantly by CYP3A. The clinical studies involved treatment of healthy volunteers (n ϭ 17-20), in a crossover design, with ketoconazole (200 mg b.i.d.) or fluconazole (400 mg once a day), while receiving MLN3897. Administration of MLN3897 and ketoconazole led to an average 8.28-fold increase in area under the curve of plasma concentration-time plot (AUC) of MLN3897 at steady state, compared with the 8.33-fold increase predicted from the in vitro data. Similarly for fluconazole, an average increase of 3.93-fold in AUC was observed for MLN3897 in comparison with a predicted value of 3.26-fold. Thus, our model reliably predicted the exposure changes for MLN3897 in interaction studies with competitive CYP3A inhibitors in humans, further strengthening the utility of our in vitro model. Prediction of clinical DDIs using in vitro studies is one of the major challenges in the pharmaceutical industry. The main utility of such DDI predictions is to help foresee any safety issues anticipated from higher exposures and thus help design clinical trials with better safety. In some instances, clinical DDI studies can be avoided if no significant pharmacokinetic interaction is predicted. Traditionally, DDI predictions have been based on the ratio of the inhibitor concentration [I] and the enzyme inhibition constant K i ([I]/K i ratio

Clinically Relevant Interactions between Newer Antidepressants and Second-Generation Antipsychotics

INTRODUCTION: Combinations of newer antidepressants and second-generation antipsychotics (SGAs) are frequently used by clinicians. Pharmacokinetic drug interaction (PK DI) and poorly understood pharmacodynamic (PD) drug interaction (PD DI) can occur between them. AREAS COVERED: This paper comprehensively reviews PD DI and PK DI studies. EXPERT OPINION: More PK DI studies are needed to better establish dose correction factors after adding fluoxetine and paroxetine to aripiprazole, iloperidone and risperidone. Further PK DI studies and case reports are also needed to better establish the need for dose correction factors after adding i) fluoxetine to clozapine, lurasidone, quetiapine and olanzapine; ii) paroxetine to olanzapine; iii) fluvoxamine to asenapine, aripiprazole, iloperidone, lurasidone, olanzapine, quetiapine and risperidone; iv) high sertraline doses to aripiprazole, clozapine, iloperidone and risperidone: v) bupropion and duloxetine to aripiprazole, clozapine, iloperidone and risperidone; and vi) asenapine to paroxetine and venlafaxine. Possible beneficial PD DI effects occur after adding SGAs to newer antidepressants for treatment-resistant major depressive and obsessive-compulsive disorders. The lack of studies combining newer antidepressants and SGAs in psychotic depression is worrisome. PD DIs between newer antidepressants and SGAs may be more likely for mirtazapine and bupropion. Adding selective serotonin reuptake inhibitors and SGAs may increase QTc interval and may very rarely contribute to torsades de pointes

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces

Does Compound I Vary Significantly between Isoforms of Cytochrome P450?

status: publishe

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence