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      Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.

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          Abstract

          Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions.

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          Origin and physiological roles of inflammation.

          Ruslan Medzhitov (2008)
          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            IFNalpha activates dormant haematopoietic stem cells in vivo.

            Marieke Essers, Sandra Offner, William E. Blanco-Bose … (2009)
            Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
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              The IL-1 family: regulators of immunity.

              John E. Sims, Dirk Smith (2010)
              Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                Publisher: Springer Nature
                ISSN (Electronic): 1476-4679
                ISSN (Print): 1465-7392
                Publication date (Electronic): Jun 2016
                Volume: 18
                Issue: 6
                Affiliations
                [1 ] The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
                [2 ] Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
                [3 ] Division of Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
                [4 ] Department of Cell Biology, Albert Einstein Medical College, Queens, New York 10461, USA.
                [5 ] Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.
                Article
                Publisher Item ID: ncb3346 Mid ID: NIHMS772726
                DOI: 10.1038/ncb3346
                PMC ID: 4884136
                PubMed ID: 27111842
                SO-VID: ae491685-34ef-4522-aa19-cb0d33a96308
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