NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines.
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-gamma(+) [IFN-gamma(+)]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-gamma, IFN-gamma-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-gamma 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-gamma and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease.
Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
Kori L
KL
Wallace
Melissa A
MA
Marshall
Susan I
SI
Ramos
Joanne A
JA
Lannigan
Joshua J
JJ
Field
Robert M
RM
Strieter
Joel
J
Linden
D019264:Adoptive Transfer; D000755:Anemia, Sickle Cell / Q000276:immunology / Q000473:pathology*; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008168:Lung / Q000473:pathology*; D051379:Mice; D054367:Receptors, CXCR3 / Q000096:biosynthesis*
D018925:Chemokines; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D007371:Interferon-gamma