As unhealthy food habits continue to spread around the globe, the pandemic of obesity is evermore growing. In its wake is the rising incidence of non alcoholic steatohepatitis (NASH), an inflammatory liver condition. While the implication of the immune system is known to be critical in NASH, many mechanisms are yet to be revealed. Within the large pool of hepatic immune cells are the natural killer (NK) cells, some of the liver’s staunchest defenders.
A recent collaborative research effort, led by Professor Rachel Golub and Dr Elsa Bourayou from the Institut Pasteur-Paris Cité University, has characterized the role of hepatic NK cells during NASH and unveiled the critical role of bone marrow monocytes in the regulation of NK cell development in that context. This important study, published in Cell Reports, thus explores the intricate cellular interactions essential for maintaining liver health and managing the immune response in NASH.
The NASH stage is characterized by an accumulation of fat in the liver, alongside inflammation and damage to liver cells. Nowadays, NASH is globally recognized as a pressing health concern, posing risks of progressing to cirrhosis or liver cancer without effective management. Yet, the comprehension of the evolution and pathogenesis of this complex disease remains to this day a puzzle for the medical community. This study’s exploration into the bone marrow role in regulating immune responses during NASH represents a significant step towards solving this puzzle.
At the heart of their discoveries, the research team found that during NASH, certain signals resulting from endotoxemia—marked by increased blood levels of endotoxins often due to gut bacteria leaking into the bloodstream—activate bone marrow monocytes which increase their production of both the IL-15/IL-15Rα complex and osteopontin. These molecules are respectively crucial for the maturation and survival of NK cell precursors and monocytes within the bone marrow. Their increased levels promote an enhanced NK cell-poiesis that sustains the NK cell recruitment to the liver. There, the NK cells help in reducing fibrogenesis and direct the polarization of hepatic monocyte towards a pro-inflammatory state, thereby delaying the appearance of tissue scarring.
This study is notable not only for its elucidation of bone marrow monocytes’ pivotal role in regulating immune landscapes during NASH but also for proposing a sophisticated interplay among the gut, liver, and bone marrow. This tripartite axis effectively orchestrates the dynamics and functions of different immune cell populations and offers fresh perspectives for the control of liver inflammation.
This research notably involved innovative and methodical approaches to understand the complex mechanisms underlying NASH. The team employed a variety of experimental models, including dietary models to induce NASH in mice, which mirrors the condition’s development in humans. This approach provided a realistic context for studying the disease’s progression and the immune response. Through detailed analyses of the different cell populations and measurement of specific proteins and cytokines, the team was able to dissect the intricate interactions between bone marrow NK cells and monocytes in the context of a chronic liver disease.
Professor Golub, reflecting on the depth and breadth of their study, emphasized the transformative nature of their findings. She stated, “During NASH, endotoxemia-derived signals activate medullary monocytes, which upregulate both the IL-15/IL-15Ra 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.” This underlines the critical role of a well-coordinated gut-liver-bone marrow axis in effective management of liver inflammation and fibrosis and points to potential new therapeutic targets.
In summary, this comprehensive model of inter-organ communication marks a considerable advancement in liver disease research.
JOURNAL REFERENCE
Elsa Bourayou, Thibaut Perchet, Sylvain Meunier, Hugo Bouvier, Marie-Pierre Mailhe, Evie Melanitou, Ana Cumano, Rachel Golub, “Bone marrow monocytes sustain NK cell-poiesis during non-alcoholic steatohepatitis”, Cell Reports, 2024.
DOI: https://doi.org/10.1016/j.celrep.2024.113676.
ABOUT THE AUTHORS
Professor Rachel Golub stands at the forefront of immunological research as the leader of the “Development of Innate Lymphoid Cells (ILC) and Inflammation” research group at the Institut Pasteur. With a career dedicated to unraveling the complexities of the immune system, her pioneering work has advanced our understanding of hematopoiesis. Her contributions to the field began with her insightful characterization of the fetal compartment of hematopoietic stem cells and the mechanisms of hematopoiesis within the fetal spleen. These early discoveries laid the foundation for her subsequent research endeavors, which have increasingly focused on the biology of ILCs. Prof. Golub’s research has been instrumental in underlining the pivotal functions of the Notch signaling pathway in the differentiation of clonal ILC precursors during both fetal and adult life. This work not only deepens our comprehension of the developmental pathways of immune cells but also highlights the plasticity and adaptability of the immune system in response to environmental cues. At the heart of Prof. Golub’s scientific inquiry is her dedication to exploring how inflammation influences the development, fate, and functionality of ILCs. Her team’s current projects are exploring the critical roles that ILC populations play in a range of pathologies, including non-alcoholic steatohepatitis.
After graduating from the Grande École of engineering AgroParisTech, Dr Elsa Bourayou decided to pursue in research and started a PhD in 2019 under the supervision of Pr Rachel Golub, in the lab of Pr Ana Cumano at the Institut Pasteur. Her work focused on Natural Killer cells and their implication in nonalcoholic steatohepatitis (NASH). More specifically, she took an interest in the impact a pathological context can have on NK cell development and maturation and how this further influences the progression of the disease. Dr Bourayou’s future research will be centered on the study of the immune cell responses during cancer.
