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.

Inflammatory-driven NK cell maturation and its impact on pathology.

NK cells are innate lymphocytes involved in a large variety of contexts and are crucial in the immunity to intracellular pathogens as well as cancer due to their ability to kill infected or malignant cells. Thus, they harbor a strong potential for clinical and therapeutic use. NK cells do not require antigen exposure to get activated; their functional response is rather based on a balance between inhibitory/activating signals and on the diversity of germline-encoded receptors they express. In order to reach optimal functional status, NK cells go through a step-wise development in the bone marrow before their egress, and dissemination into peripheral organs via the circulation. In this review, we summarize bone marrow NK cell developmental stages and list key factors involved in their differentiation before presenting newly discovered and emerging factors that regulate NK cell central and peripheral maturation. Lastly, we focus on the impact inflammatory contexts themselves can have on NK cell development and functional maturation.

Signaling Pathways Tuning Innate Lymphoid Cell Response to Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and its incidence continues to rise globally. Various causes can lead to its development such as chronic viral infections causing hepatitis, cirrhosis or nonalcoholic steatohepatitis (NASH). The contribution of immune cells to HCC development and progression has been extensively studied when it comes to adaptive lymphocytes or myeloid populations. However, the role of the innate lymphoid cells (ILCs) is still not well defined. ILCs are a family of lymphocytes comprising five subsets including circulating Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s and lymphocytes tissue-inducer cells (LTi). Mostly located at epithelial surfaces, tissue-resident ILCs and NK cells can rapidly react to environmental changes to mount appropriate immune responses. Here, we provide an overview of their roles and actions in HCC with an emphasis on the importance of diverse signaling pathways (Notch, TGF-ß, Wnt/ß-catenin…) in the tuning of their response to HCC.