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Blood, 16 July 2009, Vol. 114, No. 3, pp. 667-676. Prepublished online as a Blood First Edition Paper on May 11, 2009; DOI 10.1182/blood-2009-02-205492. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-02-205492v1 114/3/667    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Wallace, K. L. Articles by Linden, J. PubMed PubMed Citation Articles by Wallace, K. L. Articles by Linden, J. Related Collections Immunobiology Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN- and CXCR3 chemokines Kori L. Wallace1, Melissa A. Marshall2, Susan I. Ramos2, Joanne A. Lannigan1, Joshua J. Field3, Robert M. Strieter2, and Joel Linden2 Departments of 1 Microbiology and 2 Medicine, University of Virginia, Charlottesville; and 3 Department of Medicine, Washington University, St Louis, MO Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69+, interferon-+ [IFN-+]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-, IFN-–inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN- and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1–/– mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN- and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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