CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia
| Autor: | Gabriela Gonzalez-Perez, Christina Arieta Kuksin, Lisa M. Minter |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Receptors CXCR4 Chemokine Immunology CD8-Positive T-Lymphocytes Biochemistry CXCR4 Mice Bone Marrow medicine Animals Humans Cytotoxic T cell Progenitor cell Aplastic anemia Immunobiology Mice Knockout Mice Inbred BALB C biology NF-kappa B Anemia Aplastic Cell Biology Hematology medicine.disease Molecular biology Mice Inbred C57BL Chemotaxis Leukocyte Disease Models Animal Haematopoiesis medicine.anatomical_structure biology.protein Female Bone marrow CD8 |
| Zdroj: | Blood. 125:2087-2094 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Aplastic anemia (AA) is a disease characterized by T-cell-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells. Physiologically, T cells migrate to the BM in response to chemokines, such as SDF-1α, the ligand for CXCR4. However, how T cells traffic to the BM in AA is poorly understood. CXCR4 is aberrantly expressed in immune-mediated diseases and its regulation by nuclear factor-κB (NF-κB) in cancer models is well documented. In this study, we show that CXCR4 is highly expressed on BM-infiltrating CD4(+) and CD8(+) T cells in a mouse model of AA. Inhibiting CXCR4 in AA mice, using CXCR4(-/-) splenocytes or AMD3100, significantly reduced BM infiltration of T cells. We also report that NF-κB occupancy at the CXCR4 promoter is enhanced in BM-infiltrating CD8(+) T cells of AA mice. Moreover, inhibiting NF-κB signaling in AA mice using Bay11 or dehydroxymethylepoxyquinomicin, or transferring p50(-/-) splenocytes, decreased CXCR4 expression on CD8(+) T cells, significantly reduced BM infiltration of T cells, and strongly attenuated disease symptoms. Remarkably, therapeutic administration of Bay11 significantly extended survival of AA mice. Overall, we demonstrate that CXCR4 mediates migration of pathogenic T cells to the BM in AA mice, and inhibiting NF-κB signaling may represent a novel therapeutic approach to treating AA. |
| Databáze: | OpenAIRE |
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