Microglia regulate adult neurogenesis via interleukin-6 trans-signaling triggered by apoptotic progenitors

In the adult hippocampus, neural progenitor cells (NPCs) proliferate before undergoing differentiation, maturation, and incorporation into the hippocampal neurocircuitry, where they contribute to diverse learning and memory processes that can be perturbed by injury, aging, and disease (1-10). Recent advances have identified microglia and interleukin-6 (IL-6) as regulators of adult hippocampal neurogenesis (AHN) (11). Despite these findings, the mechanism by which IL-6 signaling or microglia regulate neurogenesis has remained unclear. Here, we show that IL-6 trans signaling is triggered by microglial IL-6R shedding during efferocytosis, and that this mediates the transition from proliferation to neuronal differentiation in neighboring, healthy NPCs. We found that proliferating NPCs secrete IL-6 and that apoptotic NPCs are commonly found within clusters of proliferating NPCs. Next, we show that efferocytosis of apoptotic NPCs causes IL-6 receptor shedding by microglia and that IL-6 trans activation of NPCs leads to neuronal differentiation and maturation. Finally, we generated transgenic mice lacking IL-6R exclusively in microglia and found impaired neuronal maturation in the adult hippocampus and deficits in learning and memory in these mice. Our results reveal a molecular mechanism by which microglia regulate adult neurogenesis and contextualize myriad separate investigations into the role of microglia and IL-6 in neurogenesis. Our results position microglia not merely as passive responders to cell death but as active regulators of lineage specification and progenitor cell maturation within the neurogenic niche. The IL-6 trans signaling axis appears to function as a temporally gated checkpoint that coordinates niche refinement—balancing expansion with maturation and synchronizing neuronal development with microglial activation and quiescence. These results could be utilized to develop treatments in pathological contexts characterized by deficits in neurogenesis, such as Alzheimer’s disease.