Abr, a negative regulator of Rac, attenuates cockroach allergen-induced asthma in a mouse model.

Abstract

Abr deactivates Ras-related C3 botulinum toxin substrate (Rac), a master molecular switch that positively regulates many immune cell functions, by converting it to its GDP-bound conformation. In this article, we report that, in the absence of Abr function, cockroach allergen (CRA)-immunized mice experienced a fatal asthma attack when challenged with CRA. The asthma in abr(-/-) mice was characterized by increased pulmonary mucus production, elevated serum IgE, and leukocyte airway infiltration. Decreased pulmonary compliance was further documented by increased airway resistance upon methacholine challenge. Peribronchial and bronchoalveolar lavage eosinophils, key cells associated with allergic asthma, were increased in abr(-/-) mice, but adoptive transfer of this cell type from immunized mice to naive controls, followed by CRA challenge, showed that eosinophils are not primarily responsible for differences in airway resistance between controls and abr-null mutants. CD4(+) T cell numbers in the airways of CRA-challenged abr(-/-) mice also were significantly increased compared with controls, as were the Th2 T cell-secreted cytokines IL-4 and IL-5 in total lung. Interestingly, when control and abr(-/-) CD4(+) T cells from CRA-immunized mice were transferred to wild-type animals, airway resistance upon challenge with CRA was significantly higher in mice transplanted with T cells lacking Abr function. CD4(+) T cells from CRA-immunized and challenged abr(-/-) mice contained elevated levels of activated GTP-bound Rac compared with wild-type controls. Functionally, abr(-/-) CD4(+) T cells from CRA-exposed mice showed significantly enhanced chemotaxis toward CCL21. These results identify Abr-regulated CD4(+) T cell migration as an important component of severe CRA-evoked allergic asthma in mice.

• Authors: Dapeng Gong, Fei Fei, Min Lim, Min Yu, John Groffen, Nora Heisterkamp
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 9 Pg. 4514-20 (Nov 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 24058174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Abr protein, mouse
• Allergens
• Chemokine CCL21
• GTPase-Activating Proteins
• Interleukin-5
• allergen CRa, cockroach
• Methacholine Chloride
• Interleukin-4
• Immunoglobulin E
• rac GTP-Binding Proteins

Topics

• Adoptive Transfer
• Allergens (immunology)
• Animals
• Asthma (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Cell Movement (immunology)
• Chemokine CCL21
• Disease Models, Animal
• Eosinophils (immunology)
• GTPase-Activating Proteins (deficiency, genetics, metabolism)
• Immunoglobulin E (blood)
• Interleukin-4 (metabolism)
• Interleukin-5 (metabolism)
• Lung (immunology)
• Methacholine Chloride
• Mice
• Mice, Knockout
• rac GTP-Binding Proteins (metabolism)