Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.
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.
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.
Eric M
EM
Pietras
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.
Cristina
C
Mirantes-Barbeito
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.
Sarah
S
Fong
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Dirk
D
Loeffler
Division of Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
Larisa V
LV
Kovtonyuk
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.
SiYi
S
Zhang
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.
Ranjani
R
Lakshminarasimhan
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.
Chih Peng
CP
Chin
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.
José-Marc
JM
Techner
Department of Cell Biology, Albert Einstein Medical College, Queens, New York 10461, USA.
Britta
B
Will
Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.
Claus
0000-0002-0544-735X
C
Nerlov
Department of Cell Biology, Albert Einstein Medical College, Queens, New York 10461, USA.
Ulrich
U
Steidl
Division of Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
Markus G
MG
Manz
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Timm
T
Schroeder
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.
Emmanuelle
E
Passegué
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice
D007375:Interleukin-1