TY - JOUR
T1 - Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal
AU - Pietras, Eric M.
AU - Mirantes-Barbeito, Cristina
AU - Fong, Sarah
AU - Loeffler, Dirk
AU - Kovtonyuk, Larisa V.
AU - Zhang, Siyi
AU - Lakshminarasimhan, Ranjani
AU - Chin, Chih Peng
AU - Techner, José Marc
AU - Will, Britta
AU - Nerlov, Claus
AU - Steidl, Ulrich
AU - Manz, Markus G.
AU - Schroeder, Timm
AU - Passegué, Emmanuelle
N1 - Funding Information:
We thank M. Kissner and M. Lee for management of our Flow Cytometry Core Facility andmembers of the Passegué laboratory for insights and suggestions. E.M.P. was supported by NIH F32 HL106989 and K01DK098315, C.M.-B. by an Institute of Health Carlos III (ISCIII) fellowship, R.L. by a CIRM Bridges internship and M.G.M. by the SwissNational Science Foundation (310030-146528/1). E.P. and researchwere supported by a LLS Scholar Award and NIH R01 HL092471.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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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U2 - 10.1038/ncb3346
DO - 10.1038/ncb3346
M3 - Article
C2 - 27111842
AN - SCOPUS:84964303619
SN - 1465-7392
VL - 18
SP - 607
EP - 618
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -