Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.DOI: http://dx.doi.org/10.7554/eLife.10066.001

Objectiv eTo summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics.MethodsExperts in ‘interval imaging’ (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed.ResultsMeningioma and glioma were identified as priorities for interval imaging utility analysis. The “monitoring biomarkers” most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value.ConclusionEvidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BKC a) potassium channels which leads to membrane depolarization, voltage‐gated Ca‐entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca2+]i‐signaling in isolated neonatal rat type‐1 cells. PK‐THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK‐THPP, A1899 and Ml 365 all evoked a rapid increase in type‐1 cell [Ca2+]i. These [Ca2+]i responses were abolished in Ca2+‐free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage‐gated Ca2+‐entry mediated the rise in [Ca2+]i. Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type‐1 cell TASK channel activity and increased [Ca2+]i.. We also tested the effects of combined inhibition of BKC a and TASK channels. TEA (5 mmol/L) slightly increased [Ca2+]i in the presence of PK‐THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca2+]i in the presence of A1899 but not in the presence of PK‐THPP. In general [Ca2+]i responses to TASK inhibitors, alone or in combination with BKC a inhibitors, were smaller than the [Ca2+]i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage‐gated Ca2+‐entry but suggest that this, even with concomitant inhibition of BKC a channels, may be insufficient to account fully for the [Ca2+]i‐response to hypoxia.

HighlightsThe intravenous anaesthetic propofol acts directly on carotid body glomus cells to inhibit their response to hypoxia.Propofol acts via novel mechanisms, as we excluded action via its known target receptors (nicotinic, GABA-ergic, or K+ channel).Inhibition of the hypoxic response is clinically relevant in anaesthesia.