3023 – CCR5 ANTAGONISM REDUCES INFLAMMATORY MACROPHAGES IN BONE MARROW AND PROTECTS MICE FROM SEVERE APLASTIC ANEMIA

Severe aplastic anemia (SAA) is an acquired bone marrow failure disease associated with elevated interferon-gamma (IFNγ) and hematopoietic stem cells (HSC) loss. Treatment for SAA includes immunosuppressive therapy (IST) or HSC transplant, though these therapies are less effective in older patients. In a murine model of SAA, IFNγ-dependent signaling in macrophages induced elevated bone marrow chemokines during SAA, with a notable increase in CCL5, or RANTES. T cells are a main producer of CCL5 and express high Ccl5 in the bone marrow during SAA, however adoptive transfer studies demonstrated that T cell-derived CCL5 was not necessary for disease. In this model of SAA, macrophages exhibited elevated Ccl5 expression and a an IFNγ-dependent increase in CCR5, the main CCL5 receptor. To evaluate CCR5 signaling in SAA pathogenesis, mice were treated with the CCR5 antagonist maraviroc. CCR5 antagonism improved mouse survival, increased platelet output, and significantly increased platelet-biased CD41hi HSCs during SAA. Mechanistically, CCR5 antagonism reduced macrophage expression of pro-inflammatory genes, such as Tnf, and CCR5 was intrinsically required for increased marrow macrophages during SAA. Key ligands for CCR5, including CCL3, CCL4, and CCL5, were elevated in the marrow of aged mice. Moreover, Ccr5 expression was increased in macrophages from aged mice and humans. These studies demonstrate that CCR5 signaling is a critical axis promoting IFNγ-dependent marrow failure in SAA. Together, our findings support a potential therapeutic benefit of CCR5 antagonism in SAA, particularly in aged patients where therapeutic interventions are limited.