NOD1 ligand administration restores optimal steady-state hematopoiesis in germ-free mice

Abstract

Abstract The microbiota is required for optimal hematopoiesis. When compared to specific-pathogen free (SPF) mice, germ free (GF) animals display decreased numbers of hematopoietic stem cells (HSC), common myeloid progenitors (CMP) and common lymphoid progenitors (CLP) in bone marrow. Muropeptides produced by both gram-negative and gram-positive bacteria are important agonists of the innate immune response and are recognized by the intracellular pattern-recognition receptors NOD1 and NOD2. In the present study, we examined both direct and indirect effects of NOD signaling on hematopoietic homeostasis. While stimulation with NOD1 or NOD2 ligands had no effect on survival/proliferation of HSC, CMP and CLP in vitro, exposure of bone marrow-derived stroma cells (BMSC) to NOD1, but not NOD2, ligand induced expression of the differentiation factors SCF, IL-7, IL-3, Thpo and IL-6. Interestingly LPS, which is known to act directly on hematopoietic precursors, selectively induced only IL-6 in BMSC. To test the effects of NOD1 ligand in vivo, we compared groups of GF animals with and without peroral NOD1 ligand administration. NOD1 ligand treatment restored to normal levels serum concentrations of SCF, Thpo and IL-6, as well as the numbers of HSC, CMP and CLP in bone marrow. Taken together, these findings demonstrate that NOD1 ligand induces BMSC to produce cytokines that regulate the size of the major hematopoietic precursor pools. Thus, NOD1 signaling appears to be a major factor underlying the requirement for the microbiota in the maintenance of steady-state hematopoiesis. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious diseases.