Interferon-γ impairs proliferation of hematopoietic stem cells in mice

Abstract

Key Points• IFN-g impairs maintenance ofHSCs by directly reducing their proliferative capacity and impairing their restoration upon viral infection.• IFN-g induces SOCS1 expression in HSCs, which inhibits TPO-induced STAT5 phosphorylation, thereby deregulating key cell-cycle genes.Balancing the processes of hematopoietic stem cell (HSC) differentiation and selfrenewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand for peripheral blood cell supply.Here we demonstrate that the proinflammatory cytokine interferon-g (IFN-g) impairs maintenance of HSCs by directly reducing their proliferative capacity and that IFN-g impairs restoration of HSC numbers upon viral infection. We show that IFN-g reduces thrombopoietin (TPO)-mediated phosphorylation of signal transducer and activator of transcription (STAT) 5, an important positive regulator of HSC self-renewal. IFN-g also induced expression of suppressor of cytokine signaling (SOCS) 1 in HSCs, and we demonstrate that SOCS1 expression is sufficient to inhibit TPO-induced STAT5 phosphorylation. Furthermore, IFN-g deregulates expression of STAT5-mediated cell-cycle genes cyclin D1 and p57. These findings suggest that IFN-g is a negative modulator of HSC self-renewal by modifying cytokine responses and expression of genes involved in HSC proliferation. We postulate that the occurrence of BM failure in chronic inflammatory conditions, such as aplastic anemia, HIV, and graft-versus-host disease, is related to a sustained impairment of HSC self-renewal caused by chronic IFN-g signaling in these disorders. (Blood. 2013;121(18):3578-3585)

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

“…This result is in good agreement with previous findings, in which whole BM cells from INF-g-treated mice showed reduced engraftment 27 and ex vivo IFN-g-expanded KSL cells failed to engraft. 40 Although KSL and SKSL cells are enriched for functional HSCs in normal mice, [48][49][50] there were precedents in the literature for marked phenotype/function discordance. [51][52][53] IFN-g stimulates Sca-1 expression, 26,54 and HSCs and progenitor cells can be defined by other cell surface markers.…”

Mechanisms of self-renewal in hematopoietic stem cells

“…In addition to molecules that maintain the G0 state or support self-renewal in HSCs, molecules are desired that drive HSCs into the cell cycle or revert HSCs back to the G0 state IFN-γ was also found to stimulate quiescent HSCs in vivo [72]. However, the culture of highly purified HSCs in vitro showed the suppressive effect of IFN-γ, and virus infection induced a delayed recovery of the HSC pool [73], consistent with in vitro culture data with progenitor cells [64,67]. More recently, Pietras et al attempted to clarify this paradoxical effect of IFN on HSCs.…”

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

“…Although several studies have explored this question, their models used IFN-g that was either added exogenously or expressed by non-IFN-g-expressing cells. 11,12 Therefore, our laboratory developed an animal model whereby IFN-g is expressed by natural killer (NK) and T cells, which normally express IFN-g and will allow us to better investigate the mechanisms of how IFN-g contributes to the development of AA. Our BALB/c mouse model contains a 162-nucleotide targeted substitution in the 39 untranslated region of the IFN-g gene that eliminates the adenylateuridylate-rich element (ARE) of the IFN-g messenger RNA (mRNA) (mice are designated as ARE-del).…”