CXCR4^high megakaryocytes regulate host-defense immunity against bacterial pathogens

Area of Science:

• Immunology
• Hematology
• Cell Biology

Background:

• Megakaryocytes (MKs) are primarily known for platelet production and maintaining hematopoietic stem cells.
• The role of MKs in inflammatory and immune responses is not well understood.
• A specific subpopulation of MKs with immune functions is yet to be fully characterized.

Purpose of the Study:

• To identify and characterize novel subpopulations of megakaryocytes involved in immune responses.
• To elucidate the mechanisms by which MKs contribute to host defense against bacterial infections.
• To investigate the origin and function of CXCR4-high MKs during infection.

Main Methods:

• Single-cell RNA sequencing to identify distinct MK subpopulations.
• Co-culture experiments with myeloid cells to assess cell-cell interactions.
• In vivo bacterial infection models (Listeria monocytogenes) in mice.
• Hematopoietic stem/progenitor cell lineage tracing to determine cell origin.

Main Results:

• A subpopulation of megakaryocytes with high CXCR4 expression (CXCR4high MKs) was identified, exhibiting both MK and immune cell characteristics.
• CXCR4high MKs promote myeloid cell migration, enhance bacterial phagocytosis by macrophages and neutrophils via TNFα and IL-6 production, and present antigens to activate T cells.
• These CXCR4high MKs egress circulation and infiltrate organs like the spleen, liver, and lungs during bacterial infection.
• Ablation of MKs impaired innate immunity and T cell activation, compromising anti-bacterial defense in mice.
• CXCR4high MKs arise from infection-induced emergency megakaryopoiesis.

Conclusions:

• CXCR4high MKs represent a distinct cell population with significant roles in innate and adaptive immunity against bacterial pathogens.
• These findings reveal a novel function for megakaryocytes in regulating host-defense immune responses.
• Targeting CXCR4high MKs could offer new therapeutic strategies for bacterial infections.