Smart, J. | bioRxiv Science

bioRxiv2022

Endothelial Caspase-9 Promotes Glial Changes, Inflammation, and Contrast Sensitivity Decline in Retinal Vascular Injury

Retinal glial cells-- microglia, astrocytes, and Muller glia--provide homeostatic support, regulate vascular blood flow, and react to injury by releasing inflammatory cytokines. Glial reactivity has been shown to be relevant for retinal vascular pathology and neuronal death. Non-apoptotic expression of endothelial caspase-9 (EC Casp9) was recently identified as a key mediator of retinal edema, hypoxic-ischemic injury, and neurodegeneration in retinal vein occlusion (RVO). In the current study we aimed to determine the glial responses that are modulated by EC Casp9 as a means to identify relevant neuro-immune mechanisms for the development of retinal edema and neurodegeneration. To this end we used a mouse model of RVO and a tamoxifen inducible EC Casp9 KO mouse line. We show that EC Casp9 leads to an increase in reactive microglia and to macrogliosis in a time-dependent manner. RVO induced an EC Casp9 dependent astroglial caspase-6 and cleavage of GFAP. Cytokine array analysis revealed that RVO increases expression of inflammatory cytokines out of which CX3CL1, IGF-1, IL-4, LIX, IL-1, M-CSF, TNF-, IL-1{beta}, IL-10, and VEGF-A, were regulated by EC Casp9. Moreover, we found that EC Casp9 deletion resulted in protection from contrast sensitivity decline one day post-RVO. These results demonstrate that caspase-9 in hypoxic endothelial cells regulates retinal inflammatory signaling in microglia, astrocytes and Muller cells and changes in visual function.

neuroscience↗

bioRxiv2021

Detecting change in interconnected ecosystem assets to inform indicators of condition in environmental economic accounts

There is an increasing need for long-term monitoring of ecosystems and their services to inform on-ground management and policy direction. The supply of many ecosystem services relies on connections that span multiple ecosystems. Monitoring the underlying condition of interconnected ecosystems, using established indicators, is therefore required to track effectiveness of past interventions and, ideally, identify impending change. Here we conduct performance testing of ecological indicators for a catchment-to-coast system with the aim of identifying the time-scales over which they respond to change. We chose a case-study of a coastal fishery in Northern Australia that exhibits strong catchment-to-coast connectivity, has long-term available data and is under threat from water resource development. We developed a novel approach to performance testing. Our model drew on state-space modelling to capture ecological dynamics, and structural equation modelling to capture covariation in indictors timeseries. We first quantified covariation among three established ecological indicators: pasture biomass, vegetation greenness and barramundi catch per unit effort. Covariation in the indicators was driven by river flow, with higher values of all indicators occurring in years with greater river flow. We then defined reference bounds for each indicator that accounted for natural variation in river flow. We predicted the emergence times for each indicator, as the time taken for each indicator to emerge from the background of natural variation. Emergence times quantified at 80% and higher confidence levels were >10 years in all cases. Past trends and current status of ecosystem service flows are often used by decision makers to directly inform near-term actions, particularly provisioning services (such as barramundi catch) due to their important contribution to regional economies. We found that the ecological indicators should be used to assess historical performance over decadal timespans, but not as short-term indicators of recent change. More generally, we offer an approach to performance testing of indicators. This approach could be useful for quantifying time-scales of ecosystem response in other systems where cross-ecosystem connections are important.

ecology↗