NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines

• Published in: Blood Vol. 114; no. 3; pp. 667 - 676
• Main Authors: Wallace, Kori L., Marshall, Melissa A., Ramos, Susan I., Lannigan, Joanne A., Field, Joshua J., Strieter, Robert M., Linden, Joel
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 16.07.2009; Americain Society of Hematology; American Society of Hematology
• Series: Red Cells, Iron, and Erythropoiesis
• Subjects: Adoptive Transfer; Anemia, Sickle Cell - immunology; Anemia, Sickle Cell - pathology; Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Chemokines - biosynthesis; Diseases of red blood cells; Hematologic and hematopoietic diseases; Humans; Inflammation - etiology; Interferon-gamma - biosynthesis; Interferon-gamma - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - transplantation; Lung - pathology; Medical sciences; Mice; Receptors, CXCR3 - biosynthesis; Red Cells, Iron, and Erythropoiesis; Human; Natural killer T cell; Acquired immunity; Lung; Rodentia; Biosynthesis; Cellular immunity; Inflammation; Chemokine receptor; Natural killer cell; Vertebrata; Mammalia; Mouse; Animal; Gamma interferon; Biological receptor; CXCR3 chemokine receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-205492

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-γ+ [IFN-γ+]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-γ, IFN-γ–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-γ 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-γ and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease.