Chemokine-dependent T cell migration requires aquaporin-3–mediated hydrogen peroxide uptake

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Abstract

The water/glycerol channel aquaporin-3 is required for chemokine-dependent T cell migration during immune responses.

Abstract

Chemokine-dependent trafficking is indispensable for the effector function of antigen-experienced T cells during immune responses. In this study, we report that the water/glycerol channel aquaporin-3 (AQP3) is expressed on T cells and regulates their trafficking in cutaneous immune reactions. T cell migration toward chemokines is dependent on AQP3-mediated hydrogen peroxide (H ₂O ₂) uptake but not the canonical water/glycerol transport. AQP3-mediated H ₂O ₂ transport is essential for the activation of the Rho family GTPase Cdc42 and the subsequent actin dynamics. Coincidentally, AQP3-deficient mice are defective in the development of hapten-induced contact hypersensitivity, which is attributed to the impaired trafficking of antigen-primed T cells to the hapten-challenged skin. We therefore suggest that AQP3-mediated H ₂O ₂ uptake is required for chemokine-dependent T cell migration in sufficient immune response.

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Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes.

Gerd Bienert, Anders L B Møller, Kim A Kristiansen … (2007)

The metabolism of aerobic organisms continuously produces reactive oxygen species. Although potentially toxic, these compounds also function in signaling. One important feature of signaling compounds is their ability to move between different compartments, e.g. to cross membranes. Here we present evidence that aquaporins can channel hydrogen peroxide (H2O2). Twenty-four aquaporins from plants and mammals were screened in five yeast strains differing in sensitivity toward oxidative stress. Expression of human AQP8 and plant Arabidopsis TIP1;1 and TIP1;2 in yeast decreased growth and survival in the presence of H2O2. Further evidence for aquaporin-mediated H2O2 diffusion was obtained by a fluorescence assay with intact yeast cells using an intracellular reactive oxygen species-sensitive fluorescent dye. Application of silver ions (Ag+), which block aquaporin-mediated water diffusion in a fast kinetics swelling assay, also reversed both the aquaporin-dependent growth repression and the H2O2-induced fluorescence. Our results present the first molecular genetic evidence for the diffusion of H2O2 through specific members of the aquaporin family.

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Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling.

Evan Miller, Bryan Dickinson, Christopher Chang (2010)

Hydrogen peroxide (H(2)O(2)) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H(2)O(2) to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H(2)O(2) into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new chemoselective fluorescent indicator for H(2)O(2), directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H(2)O(2) specifically through membranes in mammalian cells. Moreover, we show that intracellular H(2)O(2) accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H(2)O(2) signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H(2)O(2) can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.

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Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption.

Samira Saadoun, Marios Papadopoulos, Mariko Hara-Chikuma … (2005)

Aquaporin-1 (AQP1) is a water channel protein expressed widely in vascular endothelia, where it increases cell membrane water permeability. The role of AQP1 in endothelial cell function is unknown. Here we show remarkably impaired tumour growth in AQP1-null mice after subcutaneous or intracranial tumour cell implantation, with reduced tumour vascularity and extensive necrosis. A new mechanism for the impaired angiogenesis was established from cell culture studies. Although adhesion and proliferation were similar in primary cultures of aortic endothelia from wild-type and from AQP1-null mice, cell migration was greatly impaired in AQP1-deficient cells, with abnormal vessel formation in vitro. Stable transfection of non-endothelial cells with AQP1 or with a structurally different water-selective transporter (AQP4) accelerated cell migration and wound healing in vitro. Motile AQP1-expressing cells had prominent membrane ruffles at the leading edge with polarization of AQP1 protein to lamellipodia, where rapid water fluxes occur. Our findings support a fundamental role of water channels in cell migration, which is central to diverse biological phenomena including angiogenesis, wound healing, tumour spread and organ regeneration.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 24 September 2012

Volume: 209

Issue: 10

Pages: 1743-1752

Affiliations

[1 ]Department of Dermatology , [2 ]Center for Innovation in Immunoregulative Technology and Therapeutics , and [3 ]Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

[4 ]Innovative Beauty Science Laboratory, Kanebo Cosmetics Inc., Odawara, Kanagawa 250-0002, Japan

[5 ]Department of Medicine and [6 ]Department of Physiology, University of California, San Francisco, San Francisco, CA 94143

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CORRESPONDENCE Mariko Hara-Chikuma: haramari@ 123456kuhp.kyoto-u.ac.jp

Article

Publisher ID: 20112398

DOI: 10.1084/jem.20112398

PMC ID: 3457725

PubMed ID: 22927550

SO-VID: 6e674a4b-1e5b-42a1-85a3-4a6506207aaa

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Chemokine-dependent T cell migration requires aquaporin-3–mediated hydrogen peroxide uptake

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Gamma Delta T cells

Most cited references 31

Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes.

Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling.

Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption.

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