Bone marrow monocytes sustain NK cell-poiesis during non-alcoholic steatohepatitis

Natural killer (NK) cells are the predominant lymphocyte population in the liver. At the onset of non-alcoholic steatohepatitis (NASH), an accumulation of activated NK cells is observed in the liver in parallel with inflammatory monocyte recruitment and an increased systemic inflammation. Using in vivo and in vitro experiments, we unveil a specific stimulation of NK cell-poiesis during NASH by medullary monocytes that trans-present interleukin-15 (IL-15) and secrete osteopontin, a biomarker for patients with NASH. This cellular dialogue leads to increased survival and maturation of NK precursors that are recruited to the liver, where they dampen the inflammatory monocyte infiltration. The increase in the production of both osteopontin and the IL-15/IL-15Rα complex by bone marrow monocytes is induced by endotoxemia. We propose a tripartite gut-liver-bone marrow axis regulating the immune population dynamics and effector functions during liver inflammation. [Display omitted] •Endotoxemia promotes IL-15/IL-15Rα and osteopontin expressions in medullary monocytes•The NK cell/monocyte dialogue enhances NK precursor maturation and survival•NK precursors recirculate and are recruited to the liver•Liver NK cells limit fibrogenesis and polarize monocytes Bourayou et al. demonstrate that, during NASH, endotoxemia-derived signals activate medullary monocytes, which upregulate both the IL-15/IL-15Rα complex and osteopontin, promoting NK precursor maturation and survival. These NK precursors exit the bone marrow and join the liver, where they dampen fibrogenesis and polarize recruited monocytes toward an M1-like phenotype.