β-Arrestin-2 regulates the development of allergic asthma
Julia K.L. Walker, … , David A. Schwartz, Robert J. Lefkowitz
Julia K.L. Walker, … , David A. Schwartz, Robert J. Lefkowitz
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):566-574. https://doi.org/10.1172/JCI17265.
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β-Arrestin-2 regulates the development of allergic asthma

Abstract

Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to their inflammatory function and is regulated in large part by chemokine receptors, members of the seven-membrane-spanning receptor family. It has been reported recently that T cells lacking β-arrestin-2, a G protein–coupled receptor regulatory protein, demonstrate impaired migration in vitro. Here we show that allergen-sensitized mice having a targeted deletion of the β-arrestin-2 gene do not accumulate T lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma. In contrast, the airway inflammatory response to LPS, an event not coordinated by Th2 cells, is fully functional in mice lacking β-arrestin-2. β-arrestin-2–deficient mice demonstrate OVA-specific IgE responses, but have defective macrophage-derived chemokine–mediated CD4+ T cell migration to the lung. This report provides the first evidence that β-arrestin-2 is required for the manifestation of allergic asthma. Because β-arrestin-2 regulates the development of allergic inflammation at a proximal step in the inflammatory cascade, novel therapies focused on this protein may prove useful in the treatment of asthma.

Authors

Julia K.L. Walker, Alan M. Fong, Barbara L. Lawson, Jordan D. Savov, Dhavalkumar D. Patel, David A. Schwartz, Robert J. Lefkowitz

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Effect of genotype and OVA treatment on lung cytokine release in whole-l...
Effect of genotype and OVA treatment on lung cytokine release in whole-lung lavage fluid. (a) Cytokines associated with a Th2-type response were significantly elevated in WT-OVA mice relative to βarr2–/–-OVA mice and alum-treated mice of either genotype. Black bars represent WT-OVA mice; white bars represent βarr2–/–-OVA mice. Cytokine levels in alum-treated WT and alum-treated βarr2–/– mice were not different and therefore were combined as shown by gray bars. Data are mean ± SEM calculated from three independent experiments; n = 11–19 mice per group. *P < 0.05 versus all other groups. (b) Cytokines associated with a Th1-type response were not significantly elevated by OVA treatment and were similar for WT and βarr2–/– mice. Black bars represent WT-OVA mice; white bars represent βarr2–/–-OVA mice. Light gray bars represent alum-treated WT mice; dark gray bars represent βarr2–/– mice. Data are mean ± SEM calculated from two to three independent experiments; n = 7–13 mice per group.