Impaired production of blood cells is associated with morbidity and mortality. The classical model for blood cell replenishment is changing with the unexpected realization that long-term hematopoietic stem cells (LT-HSCs) directly sense and respond to pathogens via toll-like receptors (TLRs). Following TLR stimulation, LT-HSCs proliferate and preferentially undergo myeloid-specific differentiation. Direct sensing of TLR ligand is thought to enable HSCs to replenish innate immune cells that are rapidly depleted during infection. However, in contrast to the potential benefits of short-term HSC activation, chronic TLR stimulation dramatically impairs long-term HSC function. We recently showed that murine HSCs chronically exposed to low-dose TLR4 agonist in vivo hyperproliferate, exhibit myeloid skewing, and fail to self-renew. These observations have important implications because TLR4 can be activated by plasma lipopolysaccharide (LPS) present in patients with chronic infection as well as by both LPS and dietary lipids that are chronically elevated in patients suffering from obesity. However, the cellular and molecular mechanisms underlying TLR4-mediated HSC exhaustion remain largely unknown.
In Aim 1, we determine the role of inflammatory cytokines, and the cellular source of TLR4 sensing, in each a defined experimental model of chronic LPS-mediated HSC skewing and in the disease model of obesity.
In Aim 2, we examine the molecular mechanisms underlying HSC skewing. These studies will be the first to establish the cellular and molecular mechanisms by which TLR stimulation impairs HSC function, and will open new areas of investigation into the mechanisms that preserve HSC integrity in health and disease.

Public Health Relevance

Persistent stimulation of toll-like receptors occurs in patients with chronic infection as well as the obese disease condition, likely contributing to morbidity and mortality. These mechanistic studies will lay the groundwork for pharmacological therapies aimed at reversing stem cell impairment to restore full immune cell potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI079047-06A1
Application #
9107580
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
2009-03-01
Project End
2016-07-31
Budget Start
2015-08-11
Budget End
2016-07-31
Support Year
6
Fiscal Year
2015
Total Cost
$377,551
Indirect Cost
$128,801
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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