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Overview

AbstractThe glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin‐4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER‐271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER‐271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion‐weighted MRI. Furthermore, AER‐271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER‐271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild‐type but not in AQP4 deficient mice, we foresee AER‐271 as a new tool for manipulation of the glymphatic system in rodent brain.

01 May 2023·The Journal of Immunology

Water channel Aquaporin 4 is required for T cell activation.

Author: Beavers, Ashley ; Kish, Danielle ; McGuirk, Paul R ; Valujskikh, Anna ; Fairchild, Robert L ; Pelletier, Marc F ; Farr, George W ; Nicosia, Michael

AbstractAquaporins are a family of ubiquitously expressed transmembrane water channels. We have previously reported that Aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. The goal of this study was to identify mechanisms of prolonged graft survival following AQP4 blockade.Stimulation of murine WT T cells + AER-270 or AQP4 −/−T cells resulted in decreased expression of T cell activation markers CD25 and CD44, and reduced cell volume when compared to control WT T cells. In addition, the absence or inhibition of AQP4 also limited IL-2 production by T cells following stimulation. Intact AQP4 was also required for optimal IFNg production by T cells. Analogously, AQP4 inhibition significantly limited the ability of human T cells to proliferate following TCR stimulation. We then examined the role of AQP4 in TCR signal transduction and found that AQP4 was required for nuclear translocation of NF-KB and NFAT and for optimal calcium flux following TCR stimulation. Either the absence or inhibition of AQP4 impaired TCR signal transduction as early as phosphorylation of Lck (pY394), ZAP70 (pY319) and LAT (p171). AQP4 was previously shown to associate with the actin cytoskeleton in other cell types, we next tested its involvement in TCR polarization/capping. We found that loss of AQP4 resulted in significantly impaired TCR capping and dysfunctional post-TCR stimulation actin remodeling kinetics.Our findings reveal novel mechanisms underlying the importance of AQP4 in optimal T lymphocyte activation and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation in solid organ transplantation and other diseases.

01 May 2022·The Journal of Immunology

Aquaporin 4 Is A Mediator Of Essential Dendritic Cell Function

Author: Valujskikh, Anna ; Beavers, Ashley ; Yamamoto, Yosuke ; Thompson, Trevor ; Zindrick, Thomas ; Nicosia, Michael

AbstractAquaporins are transmembrane water channels implicated in a range of physiologic functions. We previously reported that Aquaporin 4 (AQP4) is expressed by T cells and treatment with a small molecule AQP4 inhibitor (AER-270) significantly delays T cell mediated mouse heart allograft rejection. Our findings did not exclude a role for antigen presenting cells (APCs), and the purpose of this study is to investigate the requirement for AQP4 in dendritic cell (DC) functions.Stimulation with AQP4−/− spleen APCs with the addition of antigenic peptide, resulted in reduced frequencies of IFNγ producing MAR T cells compared to WT APCs. We confirmed that splenic DCs express AQP4. Bone marrow derived dendritic cells (BMDCs) from WT and AQP4−/− mice were stimulated with LPS or protein antigen, the absence or inhibition of AQP4 resulted in no defects in up-regulation of maturation markers following stimulation. WT and AQP4−/− BMDCs were pulsed with Lucifer Yellow, FITC-dextran and OVA-AF647 to assess antigen uptake with no observable defect after AQP4 inhibition or in AQP4−/− BMDCs. However, AQP4−/− BMDCs pulsed with OVA protein had reduced expression of SIINFEKL peptide-MHC-I complexes. In contrast, when pulsed with OVA-derived SIINFEKL peptide, AER-270 treated WT BMDCs or AQP4−/− BMDCs showed no change in peptide-MHC complex expression suggesting a role for AQP4 in antigen processing. Consistent with this, the absence or inhibition of AQP4 resulted in decreased DQ-OVA signal, indicating that AQP4 is required for the antigen loading into the lysosome.Our data indicate that AQP4 plays a critical role in the processing of antigens by dendritic cells that impacts their ability to prime T cells, and can be therapeutically targeted in a transplant setting.Supported by grants from NIH (R56AI152368-01)

100 Deals associated with Aeromics, Inc.

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100 Translational Medicine associated with Aeromics, Inc.

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Pipeline

Pipeline Snapshot as of 26 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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