Hematopoietic Stem Cell Regulation by Type I and II Interferons in the Pathogenesis of Acquired Aplastic Anemia

Abstract

Aplastic anemia (AA) occurs when the bone marrow fails to support production of all three lineages of blood cells, which are necessary for tissue oxygenation, infection control, and hemostasis. The etiology of acquired AA is elusive in the vast majority of cases but involves exhaustion of hematopoietic stem cells (HSC), which are usually present in the bone marrow in a dormant state, and are responsible for lifelong production of all cells within the hematopoietic system. This destruction is immune mediated and the role of interferons remains incompletely characterized. Interferon gamma (IFNγ) has been associated with AA and type I IFNs (alpha and beta) are well documented to cause bone marrow aplasia during viral infection. In models of infection and inflammation, IFNγ activates HSCs to differentiate and impairs their ability to self-renew, ultimately leading to HSC exhaustion. Recent evidence demonstrating that IFNγ also impacts the HSC microenvironment or niche, raises new questions regarding how IFNγ impairs HSC function in AA. Immune activation can also elicit type I interferons, which may exert effects both distinct from and overlapping with IFNγ on HSCs. IFNα/β increase HSC proliferation in models of sterile inflammation induced by polyinosinic:polycytidylic acid and lead to BM aplasia during viral infection. Moreover, patients being treated with IFNα exhibit cytopenias, in part due to BM suppression. Herein, we review the current understanding of how interferons contribute to the pathogenesis of acquired AA, and we explore additional potential mechanisms by which interferons directly and indirectly impair HSCs. A comprehensive understanding of how interferons impact hematopoiesis is necessary in order to identify novel therapeutic approaches for treating AA patients.

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

“…IFNγ has been implicated in the pathophysiology of BMF syndromes (12,13). A previous study has shown that IFNγ augments the expression of Fas and other pro-apoptotic genes and causes destruction of hematopoietic cells via Fas-mediated apoptosis (14).…”

“…A pro-inflammatory milieu and sensitivity of hematopoietic stem/progenitor cells (HSPC) to inflammatory cytokines such as TNF-α, IL-6 and IFNγ have been shown to suppress normal hematopoiesis (5,11). In particular, there is significant evidence for IFNγ playing a key role in marrow failure syndromes (12)(13)(14). However, there are different theories, which are sometimes conflicting, regarding the mechanism by which IFNγ promotes BMF.…”

“…There is also very little information on the triggers that underlie upregulation of IFNγ in these marrow failure syndromes (12)(13)(14)23). Interstitial deletion of chromosome 5q is the most common cytogenetic abnormality observed in MDS, accounting for approximately 10% of all cases (25).…”

Recent advances in understanding clonal haematopoiesis in aplastic anaemia

“…Under normal circumstances, humans have approximately 11,000 haematopoietic stem cells (HSCs), up to 30% of which are estimated to actively contribute to haematopoiesis, with steady-state haematopoiesis primarily maintained by long-lived multipotent progenitors and short-term (ST) HSCs (Abkowitz, et al 2002, Busch, et al 2015, Catlin, et al 2011). In AA, immune-mediated depletion of haematopoiesis-maintaining cells, probably multipotent progenitors and ST-HSCs, leads to aplasia and cytokine-driven marrow suppression (Busch, et al 2015, Catlin, et al 2011, Smith, et al 2016). It is not known whether long-term HSCs are also directly targeted by immune-mediated destruction, or whether HSC loss occurs through attrition and differentiation.…”

The regulatory roles of VEGF‐Notch signaling pathway on aplastic anemia with kidney deficiency and blood stasis

“…Aplastic anemia (AA) is a rare and life‐threatening disease characterized by heterogeneous bone marrow (BM) failure and peripheral pancytopenia . Since BM fails to support the production of all three lineages of blood cells, AA patients are always accompanied with pancytopenia, anemia, leukopenia, and thrombocytopenia . Hematopoietic stem cell (HSC) transplantation and anti‐thymocyte globulin combined with cyclosporine A and glucocorticoids are the main therapeutic strategies in AA, while the therapeutic efficacy is still limited …”