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

Eric M. Pietras, Cristina Mirantes-Barbeito, Sarah Fong, Dirk Loeffler, Larisa V. Kovtonyuk, Siyi Zhang, Ranjani Lakshminarasimhan, Chih Peng Chin, José Marc Techner, Britta Will, Claus Nerlov, Ulrich Steidl, Markus G. Manz, Timm Schroeder, Emmanuelle Passegué

Research output: Contribution to journalArticle

170 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)607-618
Number of pages12
JournalNature Cell Biology
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Cell Biology

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    Pietras, E. M., Mirantes-Barbeito, C., Fong, S., Loeffler, D., Kovtonyuk, L. V., Zhang, S., Lakshminarasimhan, R., Chin, C. P., Techner, J. M., Will, B., Nerlov, C., Steidl, U., Manz, M. G., Schroeder, T., & Passegué, E. (2016). Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nature Cell Biology, 18(6), 607-618. https://doi.org/10.1038/ncb3346