title: Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling.
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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Burberry
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Melody Y
authors.initials: MY
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Wicks
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.affiliation: 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.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000067736:Ataxin-10; D001853:Bone Marrow / Q000382:microbiology / Q000473:pathology; D000071178:CD48 Antigen; D002352:Carrier Proteins / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D048168:Escherichia coli K12 / Q000472:pathogenicity; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000067736:Ataxin-10; C505248:Atxn10 protein, mouse; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D002352:Carrier Proteins; C000604066:Cd48 protein, mouse; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D011956:Receptors, Cell Surface; C000604059:SLAMF1 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016179:Granulocyte Colony-Stimulating Factor; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1