NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines
| Autor: | Joanne A. Lannigan, Susan I. Ramos, Kori L. Wallace, Melissa A. Marshall, Joel Linden, Robert M. Strieter, Joshua J. Field |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Chemokine
Receptors CXCR3 Immunology Inflammation chemical and pharmacologic phenomena Anemia Sickle Cell Biology CXCR3 Biochemistry Natural killer cell Interferon-gamma Mice Red Cells Iron and Erythropoiesis medicine CXCL10 Animals Humans Lung hemic and immune systems Cell Biology Hematology Natural killer T cell Adoptive Transfer Killer Cells Natural medicine.anatomical_structure biology.protein CXCL9 medicine.symptom Chemokines Cell activation |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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