Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation
Program: Oral and Poster Abstracts
Type: Oral
Session: 504. Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation: Hematopoietic Stem Cell Regulation By Cytokine Signaling
Program: Oral and Poster Abstracts
Type: Oral
Session: 504. Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation: Hematopoietic Stem Cell Regulation By Cytokine Signaling
Monday, December 7, 2015: 5:15 PM
W312, Level 3
(Orange County Convention Center)
Hematopoietic stem cells (HSCs) maintain lifelong blood homeostasis. While many of the cell-intrinsic mechanisms regulating HSC function at steady state have been well characterized, the role of inflammatory cytokines and other environmental factors in tailoring blood production following physiological insults has become a topic of emerging interest. The cytokine interleukin-1 (IL-1) is a prototypical pro-inflammatory cytokine that plays a key role in host inflammatory responses to injury and infection, and is associated with elevated myeloid cell production. Importantly, IL-1 also drives a wide range of chronic inflammatory conditions such as diabetes, obesity, and arthritis that are often characterized by deregulated blood homeostasis. Here, we show at single-cell resolution using continuous tracking technology that IL-1 drives accelerated HSC cell division kinetics and myeloid differentiation via the rapid activation of a precocious PU.1-dependent myeloid gene program. Activation of this program requires direct IL-1R signaling and subsequent activation of IKK kinases, and instructively primes HSCs to adopt a myeloid fate. Strikingly, we demonstrate that IL-1 produced by myeloid cells and endothelial cells of the bone marrow (BM) niche exerts similar effects in vivo, and is required for efficient myeloid recovery following acute challenges such as transplantation or myeloablation. On the other hand, we find that chronic IL-1 exposure substantially remodels HSC blood output, resulting in myeloid overproduction and expansion of myeloid-biased multipotent progenitor (MPP) compartments at the expense of lymphoid and erythroid lineages. Critically, chronic IL-1 erodes HSC self-renewal, significantly impairing their regenerative capacity following transplantation. On the other hand, chronically exposed HSCs recover their function upon IL-1 withdrawal. Collectively, these findings identify IL-1 as a critical regulator of HSC fate and lineage specification via activation of a PU.1 circuit. They also demonstrate a role for IL-1 as a double-edged sword in HSC biology, promoting HSC regeneration in response to acute insults while severely disrupting HSC self-renewal and lineage output during chronic exposure, hence identifying IL-1 as an important and therapeutically targetable factor underwriting myeloid overproduction and other deregulations that contribute to the pathogenesis of a variety of chronic inflammatory diseases and blood disorders.
Disclosures: No relevant conflicts of interest to declare.
See more of: 504. Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation: Hematopoietic Stem Cell Regulation By Cytokine Signaling
See more of: Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation
See more of: Oral and Poster Abstracts
See more of: Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation
See more of: Oral and Poster Abstracts
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