Type II Interferon Promotes Differentiation of Myeloid-Biased Hematopoietic Stem Cells

Abstract

Interferon gamma (IFNγ) promotes cell division of hematopoietic stem cells (HSCs) without affecting the total HSC number. We postulated that IFNγ stimulates differentiation of HSCs as part of the innate immune response. Here we report that type II interferon signaling is required, both at baseline and during an animal model of LCMV infection, to maintain normal myeloid development. By separately evaluating myeloid-biased and lymphoid-biased HSC subtypes, we found that myeloid-biased HSCs express higher levels of IFNγ receptor and are specifically activated to divide after recombinant IFNγ exposure in vivo. HSCs show increased expression of the transcription factor C/EBPβ after infection. Furthermore, myeloid-biased HSCs are transiently depleted from the marrow during the Type II interferon-mediated immune response to Mycobacterium avium infection, as measured both functionally and phenotypically. These findings indicate that IFNγ selectively promotes differentiation of myeloid-biased HSCs during an innate immune response to infection. This represents the first report of a context and a mechanism for discriminate utilization of the alternate HSC subtypes. Terminal differentiation, at the expense of self-renewal, may compromise HSC populations during states of chronic inflammation.

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

“…30 We thus measured the serum IFNa concentration in miR-22 KO and WT animals on day 3 following infection. Notably, WT animals mounted a strong IFNa response, while the IFNa levels in miR-22 KO were significantly lower (Figure 2C) 29 . Additionally, miR-22 KO animals demonstrated no baseline elevation in IFNa and no induction of IFNa at day 6 post-infection (Figure 2C, data not shown).…”

“…MicroRNAs are frequently devoid of phenotypes in absence of stress, therefore we next compared peripheral blood immune cell numbers in miR-22 KO versus WT mice 6 days after a non-lethal short-term LCMV infection which is near the peak of response in blood 29 . Notably, platelets were depleted in WT animals during LCMV infection but not in miR-22 KO animals (Figure 1D).…”

“…Normally LCMV elicits a pronounced IFNa response in mice that peaks 2–3 days after infection 29 . IFNa can then induce a cascade of cytokines including TNFa and IL1 that promote vasodilation and circulatory collapse.…”

Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation

“…We previously showed that IFNγ stimulates cell division of HSCs in a murine model of Mycobacterium avium infection, leading to a defect in repopulation capacity (Baldridge et al, 2010). Furthermore, short-term IFNγ-mediated HSC division appears to accelerate differentiation during infection (Matatall et al, 2014); however, both the long-term impact and the mechanism of these processes remains unknown.…”

Interferons Coordinate a Multifaceted Defense

“…IFN stimulation leads to increased proliferation and differentiation of hematopoietic progenitors, suggesting a role for stem cells in building the army of immune cells needed to respond to microbial invasion and injury (Matatall et al, 2014). Unlike the antiviral state in the affected tissue, these interferon responses occur remote from the site of infection and are not associated with immediate apoptosis or induction of cytotoxic responses.…”