IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation

Abstract

• IFN-g alone leads to aplastic anemia by disrupting the generation of common myeloid progenitors and lineage differentiation.• The inhibitory effect of IFN-g on hematopoiesis is intrinsic to hematopoietic stem/ progenitor cells.Aplastic anemia (AA) is characterized by hypocellular marrow and peripheral pancytopenia. Because interferon gamma (IFN-g) can be detected in peripheral blood mononuclear cells of AA patients, it has been hypothesized that autoreactive T lymphocytes may be involved in destroying the hematopoietic stem cells. We have observed AA-like symptoms in our IFN-g adenylate-uridylate-rich element (ARE)-deleted (del) mice, which constitutively express a low level of IFN-g under normal physiologic conditions. Because no T-cell autoimmunity was observed, we hypothesized that IFN-g may be directly involved in the pathophysiology of AA. In these mice, we did not detect infiltration of T cells in bone marrow (BM), and the existing T cells seemed to be hyporesponsive. We observed inhibition in myeloid progenitor differentiation despite an increase in serum levels of cytokines involved in hematopoietic differentiation and maturation. Furthermore, there was a disruption in erythropoiesis and B-cell differentiation. The same phenomena were also observed in wild-type recipients of IFN-g ARE-del BM. The data suggest that AA occurs when IFN-g inhibits the generation of myeloid progenitors and prevents lineage differentiation, as opposed to infiltration of activated T cells. These results may be useful in improving treatment as well as maintaining a disease-free status. (Blood. 2014;124(25):3699-3708)

Interferon γ (IFNγ) Signaling via Mechanistic Target of Rapamycin Complex 2 (mTORC2) and Regulatory Effects in the Generation of Type II Interferon Biological Responses

“…The signaling pathways activated by the type II IFN receptor and the mechanisms accounting for IFN␥ responses are of particular interest because of the critical role of IFN␥ in immune responses to a variety of insults. Moreover, IFN␥ overproduction has been implicated in the pathophysiology of certain diseases, especially bone marrow failure syndromes in humans (12,47,48). Therefore, precisely defining the signaling pathways downstream of the type II IFN receptor and elucidating their roles in specific biological responses has important clinical translational implications for the design of antiviral therapies and for the design of targeting approaches in bone marrow failure disorders and syndromes.…”

“…More recently, studies have focused on the identification of mechanisms by which IFNs regulate mRNA translation (49). There is accumulating evidence indicating central and essential roles for IFN-activated AKT/mTOR pathways and effector elements in type II IFNsignaling (23,24,47,50). Notably, mTOR signals are well recognized to regulate cap-dependent mRNA translation and protein expression of tumorigenic proteins and play positive roles in cytokine-induced mitogenic signaling pathways and immune signaling networks (24,29,(32)(33)(34)(35).…”

“…The specificity of this unique signaling cascade makes it an attractive target for therapeutic approaches aimed at selectively reversing the suppression of hematopoiesis resulting from IFN␥ overproduction in hematopoiesis (47,48). It is conceivable that future identification of IFN-specific signaling elements that drive the mTORC2 3 AKT 3 mTORC1 3 cap effector sequence of events will ultimately allow the development of specific therapeutic interventions to target the pathway and selectively disrupt production of ISG products that suppress hematopoiesis.…”

IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure

“…40 In another report, constitutive IFN-g expression, achieved by deletion of an IFN-g-adenylate-uridylate-rich element, resulted in AA with disruption of multilineage differentiation. 43 Gene expression analyses revealed downregulation of Gata2, Pax5, Stat3, and Ets-1 in IFN-g-expanded KSL cells; Ets-1 was downregulated in KSL cells treated with IFN-g both in vitro and in vivo. As a key member of the Ets family of transcription factors, Ets-1 is a positive regulator of hematopoietic differentiation and lineage specification.…”

Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice

“…However, we determined that these two inflammatory cytokines function in opposite ways in the pathogenesis of AAA. Ifnγ is the key effector of the autoimmune response which represses BM hematopoiesis, 20,45 whereas Tnfα is a factor which restricts autoimmune responsiveness and inhibits the progression of AAA. This observation is contrary to the currently accepted dogma for the role of TNFα in the pathogenesis of autoimmune diseases.…”