Although most hematopoietic stem cells (HSCs) reside in the bone marrow, some are located in the spleen, and some are even present in the blood and lymphatic systems. These HSC populations can replenish circulating immune cells during periods of high demand, such as systemic bacterial infection. Burberry et al. found that systemic infection of mice with Escherichia coli mobilized HSCs from the bone marrow to the spleen, resulting in a reduction in bone marrow HSCs and an increase in splenic HSCs. Compared with infected wild-type mice, fewer HSCs accumulated in the spleens of infected mice lacking Toll-like receptor 4 (TLR4) or receptor-interacting serine-threonine kinase 2 (RIPK2), a downstream effector of signaling through NOD pattern recognition receptors. Treating wild-type mice with the TLR4 agonist lipopolysaccharide (LPS) did not trigger accumulation of HSCs in spleen, but treating animals with both LPS and the NOD1 agonist KF1B did. TLR4 and NOD1 signaling functioned in radiation-resistant cells of the bone marrow niche, not in the HSCs themselves, to trigger HSC mobilization. Infection triggered an increase in the amount of circulating granulocyte colony-stimulating factor (G-CSF), a known HSC mobilizing agent, and a decrease in the abundance of CXCL12, a chemokine that promotes HSC retention in the bone marrow. Cultured bone marrow endothelial cells responded to LPS and KF1B by increasing production of G-CSF and decreasing production of CXCL12. Pretreating mice with a G-CSF–blocking antibody before treatment with LPS and KF1B prevented accumulation of HSCs in the spleen. When transplanted into mice that had been sublethally irradiated before E. coli infection, splenic HSCs from infected mice that had been pretreated with the G-CSF–blocking antibody were less effective at reducing systemic bacteria and gave rise to fewer monocytes and neutrophils compared with splenic HSCs from untreated infected donors. Thus, pathogen-induced signaling through NOD1 and TLR4 in the bone marrow niche mobilizes HSCs from the bone marrow to the spleen to help fight systemic infection. That NOD signaling influences stem cell function was also reported by Nigro et al., who found that signaling induced by a microbe-derived agonist of NOD2 promoted survival of intestinal stem cells and improved their resistance to oxidative stress–induced cell death. Commentary by Fritz addresses the implications of NOD signaling in the regulation of stem cell function.
A. Burberry, M. Y. Zeng, L. Ding, I. Wicks, N. Inohara, S. J. Morrison, G. Núñez, Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling. Cell Host Microbe 15, 779–791 (2014). [PubMed]
G. Nigro, R. Rossi, P. H. Commere, P. Jay, P. J. Sansonetti, The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15, 792–798 (2014). [PubMed]
J. H. Fritz, NOD-like receptors have a grip on stem cells. Cell Host Microbe 15, 659–661 (2014). [PubMed]