| First Author | Arieta Kuksin C | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 13 | Pages | 2087-94 |
| PubMed ID | 25647836 | Mgi Jnum | J:222051 |
| Mgi Id | MGI:5643897 | Doi | 10.1182/blood-2014-08-594796 |
| Citation | Arieta Kuksin C, et al. (2015) CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia. Blood 125(13):2087-94 |
| abstractText | 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-1alpha, 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-kappaB (NF-kappaB) 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-kappaB occupancy at the CXCR4 promoter is enhanced in BM-infiltrating CD8(+) T cells of AA mice. Moreover, inhibiting NF-kappaB 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-kappaB signaling may represent a novel therapeutic approach to treating AA. |
