The Role of Interferon, Inflammation and Infection in Aplastic Anemia

Bone marrow failure (BMF) syndromes are a group of acquired and inherited diseases characterized by failed production of blood and immune cells, and profound bone marrow aplasia. Acquired BMF, including severe aplastic anemia (SAA), has been linked to radiation, chemical exposure, and infection, and the precise mechanisms of disease likely differ on a case-by-case basis. Inflammation and immune-mediated destruction of the marrow is a key driver of SAA, thus disease management centers on immunosuppressive therapy (IST) and, especially in young patients, bone marrow transplantation (BMT). However, not all patients are good transplant candidates and IST responsiveness varies, therefore, more specific treatments are necessary. HSC loss is a key feature of SAA, though it has been unclear if inflammation depletes HSCs directly or does so through the microenvironment. Interferons (IFNs) are proteins produced in response to microbial infections that play key roles in limiting pathogen spread and eradicating infections. While transient inflammatory responses and IFN production are often necessary for appropriate host defense, elevated levels of IFN-gamma (IFNγ) have long been associated with BMF syndromes, and type I IFNs (alpha and beta) are well documented to cause bone marrow aplasia during viral infection ¹. In models of infection and inflammation IFNs can activate HSCs to proliferate and differentiate, but can also impair proliferation, and in both cases result in restricting HSC self-renewal ^2-5. The precise mechanisms whereby IFNs mediate SAA and whether IFNs act directly on HSCs have remained elusive. In a mouse model of SAA driven by T cell-derived IFNγ we found that IFNγ-dependent HSC loss was associated with reduced marrow stromal cells, but a marked preservation of bone marrow-resident macrophages (MΦs) ⁶. Our data were consistent with findings from SAA patient marrow that also demonstrates MΦ persistence, despite significant reductions in nearly all other stromal and hematopoietic cell types ⁷. Moreover, we found that IFNγ was necessary for the maintained pool of MΦs. Depleting MΦs using Clodronate-loaded liposomes, or abrogating IFNγ signaling specifically in MΦs was shown to rescue HSCs and reduce SAA-associated mortality. Targeting MΦs during SAA improved thrombocytopenia, increased BM megakaryocytes, preserved platelet-primed HSCs, and increased the platelet-repopulating capacity of transplanted HSCs ⁶. During SAA IFNγ and MΦs were required for elevated levels of particular chemokines in the bone marrow, including CCL3, CCL4, and CCL5, which were further identified as downstream targets for mitigating SAA pathogenesis. The identification of MΦ function as a key determinant of IFNγ-dependent HSC loss in SAA furthers our understanding of disease pathogenesis and illustrates an important role for the microenvironment in SAA. These studies may reveal potential therapeutic strategies to complement current treatments for SAA that avoid generalized immunosuppression and potentially improve long-term outcomes.

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