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Bone marrow CX3CR1+ mononuclear cells relay systemic microbiota signal to control hematopoietic progenitors in mice

Seungwon Lee, Hyekang Kim, Gihoon You, Young-Min Kim, Seunghun Lee, Viet-Hoan Le, Ohseop Kwon, Sin-Hyeog Im, You-Me Kim, Kwang Soon Kim, Young Chul Sung, Ki Hean Kim, Charles D. Surh, Yunji Park and Seung-Woo Lee

Key Points

  • Microbiota-derived molecules (MDMs) are concentrated in specific types of innate immune cells, CX3CR1+ mononuclear cells (MNCs), in the BM.

  • CX3CR1+ MNCs process MDMs to produce inflammatory cytokines to regulate hematopoietic progenitors in the perivascular region.

Abstract

The microbiota regulate hematopoiesis in the bone marrow (BM); however, the detailed mechanisms remain largely unknown. In this study, we explored how microbiota-derived molecules (MDMs) were transferred to the BM and sensed by the local immune cells to control hematopoiesis under steady-state conditions. We reveal that MDMs, including bacterial DNA (bDNA), reach the BM via systemic blood circulation and are captured by CX3CR1+ mononuclear cells (MNCs). CX3CR1+ MNCs sense MDMs via endolysosomal toll-like receptors (TLRs) to produce inflammatory cytokines, which control the basal expansion of hematopoietic progenitors, but not HSCs, and their differentiation potential toward myeloid lineages. CX3CR1+ MNCs co-locate with hematopoietic progenitors at the perivascular region, and the depletion of CX3CR1+ MNCs impedes bDNA influx into the BM. Moreover, the abrogation of TLR pathways in CX3CR1+ MNCs abolished the microbiota effect on hematopoiesis. These studies demonstrate that systemic MDMs control BM hematopoiesis by producing CX3CR1+ MNC-mediated cytokines in the steady-state.

  • Submitted March 7, 2019.
  • Revision received August 6, 2019.
  • Accepted July 15, 2019.