Submitted February 13, 2009
Accepted May 1, 2009
NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-
and CXCR3 chemokines
Kori L. Wallace, Melissa A. Marshall, Susan I. Ramos, Joanne A. Lannigan, Joshua J. Field, Robert M. Strieter, and Joel Linden*
Department of Microbiology, University of Virginia, Charlottesville, VA, United States
Department of Medicine, University of Virginia, Charlottesville, VA, United States
Department of Medicine, Washington University, St. Louis, MO, United States
* Corresponding author; email: jlinden{at}virginia.edu.
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 to C57BL/6 controls, NY1DD mice have more numerous and activated (CD69+, IFN-
+) lung, liver, and spleen iNKT cells that are hyper-responsive 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. Similar to mice, individuals 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.
