Aquaporin 4 inhibition alters chemokine receptor expression and T cell trafficking

Abstract

Aquaporins (AQPs) are water channels that mediate a variety of biological processes. However, their role in the immune system is poorly understood. We recently reported that AQP4 is expressed by naïve and memory T cells and that AQP4 blockade with a small molecule inhibitor prolongs murine heart allograft survival at least partially through diminishing T cell activation, proliferation and trafficking. The goal of this study was to determine how AQP4 function impacts T cells in the absence of antigen stimulation. AQP4 inhibition transiently reduced the number of circulating CD4+ and CD8+ T cells in naïve non-transplanted mice in the absence of systemic T cell depletion. Adoptive transfer studies demonstrated T cell intrinsic effect of AQP4 inhibition. AQP4 blockade altered T cell gene and protein expression of chemokine receptors S1PR1 and CCR7, and their master regulator KLF-2, and reduced chemotaxis toward S1P and CCL21. Consistent with the in vitro data, in vivo AQP4 inhibition reduced T lymphocyte numbers in the lymph nodes with simultaneous accumulation in the liver. Our findings indicate that blocking AQP4 reversibly alters T lymphocyte trafficking pattern. This information can be explored for the treatment of undesirable immune responses in transplant recipients or in patients with autoimmune diseases.

Lymphocyte egress signal sphingosine-1-phosphate promotes ERM-guided, bleb-based migration

“…Aquaporins can coordinate migration in some settings by harnessing osmotic pressure ( Stroka et al, 2014 ), and treating mice with a putative inhibitor of aquaporin 4 results in potent lymphopenia without changes in splenic T cell numbers, consistent with an egress block. These alterations were attributed to changes in gene expression, but a direct role for aquaporins in egress was not ruled out ( Nicosia et al, 2019 ). In our hands, T cells poorly tolerated inhibitors of aquaporins and solute transporters, precluding studies aimed at determining a role for osmolarity in S1P-induced pressurization or blebbing.…”

A Bioinformatics Analysis of the Potential Roles of Aquaporin 4 in Human Brain Tumors: An Immune-Related Process

“…Some studies found that inhibition of AQP4 expression resulted in slowed tumor growth ( Ding et al, 2011 ; Ding et al, 2013 ). Nicosia et al ( Nicosia et al, 2019 ) found that both CD4 + and CD8 + T cells expression AQP4. T cell proliferation, trafficking and activation were stunted as a result of AQP4 blockade.…”

Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease

“…Chemokine-dependent T-cell migration seems to require AQP3-mediated H 2 O 2 uptake [338]. The inhibition of AQP4 with AER-271 in mice T-cells reduced the expression of key chemokine receptors (S1PR1, CCR7) and impaired chemotactic activation [339]; however, evidence for this agent as a selective AQP4 inhibitor is equivocal, and the effects could reflect the inhibition of IKKβ and NF-κB signaling [340]. Phagocytosis, an ultimate defense mechanism, is supported by AQP3-mediated glycerol flux in macrophages during phagosome formation [341].…”