Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice

Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy. [Display omitted] •Psychological stress promotes myeloid differentiation of HSCs via intrinsic S100A9•Myeloid cells from bone marrow HSCs penetrate the brain in depression•Neutrophils are stimulated by AVP to return to bone marrow and augment myelopoiesis•IL-36G-IL-1RL2 axis triggers HSC myelopoiesis and exacerbates neuroinflammation Lu and colleagues find that psychological stress induces myeloid-biased differentiation of hematopoietic stem cells through neutrophils homing back to bone marrow depending on arginine vasopressin stimulation, leading to myeloid cells penetrating the brain and neuroinflammation in depression.