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CARMA1 Is Critical for the Development of Allergic Airway Inflammation in a Murine Model of Asthma¹

Benjamin D. Medoff^*,, Brian Seed, Ryan Jackobek^*, Jennifer Zora^*, Yi Yang^2,, Andrew D. Luster^* and Ramnik Xavier^3,,

^* Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; and Pulmonary and Critical Care Unit, Center for Computational and Integrative Biology, and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

CARMA1 has been shown to be important for Ag-stimulated activation of NF-B in lymphocytes in vitro and thus could be a novel therapeutic target in inflammatory diseases such as asthma. In the present study, we demonstrate that mice with deletion in the CARMA1 gene (CARMA1^–/–) do not develop inflammation in a murine model of asthma. Compared with wild-type controls, CARMA1^–/– mice did not develop airway eosinophilia, had no significant T cell recruitment into the airways, and had no evidence for T cell activation in the lung or draining lymph nodes. In addition, the CARMA1^–/– mice had significantly decreased levels of IL-4, IL-5, and IL-13, did not produce IgE, and did not develop airway hyperresponsiveness or mucus cell hypertrophy. However, adoptive transfer of wild-type Th2 cells into CARMA1^–/– mice restored eosinophilic airway inflammation, cytokine production, airway hyperresponsiveness, and mucus production. This is the first demonstration of an in vivo role for CARMA1 in a disease process. Furthermore, the data clearly show that CARMA1 is essential for the development of allergic airway inflammation through its role in T lymphocytes, and may provide a novel means to inhibit NF-B for therapy in asthma.