Cav1.4 calcium channels control cytokine production by human peripheral TH17 cells and psoriatic skin-infiltrating T cells.

BACKGROUND: Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in TH17 cells may be beneficial in psoriasis. We found that Cav1.4, encoded by CACNA1F, was the only Cav1 calcium channel expressed in TH17 cells. OBJECTIVE: We sought to investigate the role of Cav1.4 expression in early TH17-activation events and effector functions, as well as its association with TH17 signature genes in lesional psoriatic (LP) skins. METHODS: Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Cav1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Cav1.4 in TH17 activation and effector functions in a 3-dimensional skin reconstruction model. RESULTS: CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4+ and CD4- cells from LP biopsies. Nicardipine, a Cav1 channel antagonist, markedly reduced inflammatory cytokine production by TH17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Cav1.4 in TH17 cells impaired cytokine production. Finally, Cav1 inhibition reduced the expression of the keratinocyte genes characteristic of TH17-mediated psoriasis inflammation in human skin equivalents. CONCLUSIONS: Cav1.4 channels promote TH17-cell functions both at the periphery and in inflammatory psoriatic skin.

Multi-target scenario discovery to plan for sustainable food and land systems in Australia.

The development of detailed national pathways towards sustainable food and land systems aims to provide stakeholders with clarity on how long-term goals could be achieved and to reduce roadblocks in the way to making commitments. However, the inability to perfectly capture the relationships between all variables in a system and the unknown probability of future values (deep uncertainty) makes it very difficult to design scenarios that account for the full breadth of system uncertainty. Here we use scenario discovery to systematically explore the effect of different parameter ranges on model outputs, and design resilient pathways to sustainability in which multiple target achievement requires a broad portfolio of solutions. We use a model of the Australian food and land system, the FABLE (Food, Agriculture, Biodiversity, Land-use, Energy) Calculator, to investigate conditions for achieving a sustainable Australian food and land system under scenarios based on the Shared Socioeconomic Pathways (SSP) 1, 2, and 3 narratives. Here we link the FABLE Calculator with a Monte Carlo simulation tool to explore hundreds of thousands of scenarios. This allows us to identify the ranges of systemic drivers that achieve multiple sustainability targets around diets, net forest growth, agricultural water consumption, greenhouse gas emissions, biodiversity conservation, and exports by 2050. Our results show that livestock productivity and density, afforestation, and dietary change are powerful influencers for sustainability target achievement. Around 10% of the SSP1 scenarios could achieve all modelled sustainability targets. However, practically none of the scenarios based on SSP2 and SSP3 narratives could achieve such targets. The results suggest that there are options to achieve a more sustainable and resilient Australian food and land-use system with better socio-economic and environmental outcomes than under current trends. However, its achievement requires significant structural changes and coordinated interventions in several components of the domestic food and land system to increase its resilience and environmental and socio-economic performance. Understanding the bounds within which this system needs to change and operate to achieve sustainability targets will enable greater clarity and flexibility during discussions between decision-makers and stakeholders. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-022-01202-2.