D2-type dopamine receptors are required for LPS-induced acute hematopoiesis.

Hematopoietic stem and progenitor cells (HSPCs) rapidly proliferate during infection and stress to replenish immune cells, which is essential for host defense. Dopamine, released by bone marrow (BM) nerves, regulates HSPCs via D2-type dopamine receptors. However, their role in emergency hematopoiesis across organs is unclear. We show that D2-type receptors are crucial for hematopoiesis in BM, spleen, lymph nodes, and thymus. Genetic deletion of D2-type receptors in hematopoietic cells (DKO∆HC) impairs HSPC proliferation and reduces blood cell production under lipopolysaccharide (LPS) stimulation, particularly in BM and spleen. Limited defects are observed in lymphoid organs. Mechanistically, D2-type signaling modulates the LPS-activated TAK1-ERK pathway via Lck. The inhibition of Lck mimics decreased ERK phosphorylation seen in DKO∆HC HSPCs, revealing the important role of dopamine signals in LPS-TLR4-mediated responses.