Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling

Aaron Burberry; Melody Y Zeng; Lei Ding; Ian Wicks; Naohiro Inohara; Sean J Morrison; Gabriel Núñez

doi:10.1016/j.chom.2014.05.004

Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling

Cell Host Microbe. 2014 Jun 11;15(6):779-91. doi: 10.1016/j.chom.2014.05.004. Epub 2014 May 29.

Authors

Aaron Burberry¹, Melody Y Zeng¹, Lei Ding², Ian Wicks³, Naohiro Inohara¹, Sean J Morrison⁴, Gabriel Núñez⁵

Affiliations

¹ Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
² Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia Stem Cell Initiative, Columbia University Medical Center, 630 W. 168 Street, P & S, 7-513, New York, NY 10032, USA.
³ Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia.
⁴ Howard Hughes Medical Institute, Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
⁵ Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: gabriel.nunez@umich.edu.

Abstract

Adult hematopoietic stem cells (HSCs) are maintained in specialized niches within the bone marrow under steady-state conditions and mobilize for extramedullary hematopoiesis during periods of stress such as bacterial infections. However, the underlying mechanisms are unclear. We show that systemic infection of mice with Escherichia coli, commonly associated with bacteremia in humans, mobilizes functional HSCs to the spleen. Accumulation of splenic HSCs (CD150+CD48-Lin(-/low)Sca1+cKit+) was diminished in TLR4-deficient and RIPK2-deficient mice, implicating TLRs and cytosolic NOD1/NOD2 signaling in the process. Accordingly, dual stimulation of NOD1 and TLR4 in radio-resistant cells alone was sufficient to mobilize HSCs, while TLR4 expression on HSCs was dispensable. Mechanistically, TLR4 and NOD1 synergistically induced granulocyte colony-stimulating factor (G-CSF), which was required for extramedullary HSC accumulation. Mobilized HSCs and progenitor cells gave rise to neutrophils and monocytes and contributed to limiting secondary infection.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, CD / metabolism
Ataxin-10
Bone Marrow / microbiology
Bone Marrow / pathology
CD48 Antigen
Carrier Proteins / metabolism
Escherichia coli Infections / metabolism*
Escherichia coli Infections / microbiology
Escherichia coli Infections / pathology
Escherichia coli K12 / pathogenicity
Granulocyte Colony-Stimulating Factor / metabolism
Hematopoietic Stem Cell Mobilization
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / microbiology*
Mice, Inbred C57BL
Mice, Mutant Strains
Nod1 Signaling Adaptor Protein / genetics
Nod1 Signaling Adaptor Protein / metabolism*
Nod2 Signaling Adaptor Protein / metabolism
Receptors, Cell Surface / metabolism
Signaling Lymphocytic Activation Molecule Family Member 1
Spleen / microbiology
Spleen / pathology
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism*

Substances

Antigens, CD
Ataxin-10
Atxn10 protein, mouse
CD48 Antigen
CD48 protein, human
Carrier Proteins
Cd48 protein, mouse
Nod1 Signaling Adaptor Protein
Nod1 protein, mouse
Nod2 Signaling Adaptor Protein
Nod2 protein, mouse
Receptors, Cell Surface
SLAMF1 protein, human
Tlr4 protein, mouse
Toll-Like Receptor 4
Granulocyte Colony-Stimulating Factor
Signaling Lymphocytic Activation Molecule Family Member 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding