Manon BOURINET

Research team

Chronic liver diseases associated with obesity and alcohol

Contribution of NKp46+ innate lymphoid cells and regulation of their functions by CD44 during metabolic steatohepatitis

Abstract :

Metabolic dysfunction-associated liver disease (MASLD) is one of the leading causes of chronic liver disease, with a worldwide prevalence of 33% in 2022. MASLD encompasses a spectrum of liver complications ranging from steatosis (accumulation of lipids in hepatocytes) to metabolic-associated steatohepatitis (MASH), characterized by inflammation and hepatocyte death. MASH is the progressive form of the disease, which can progress to more critical stages such as fibrosis/cirrhosis and hepatocellular carcinoma. Intrahepatic (immune cells) and extrahepatic (adipose tissue and gut) players contribute to the development of MASLD. Currently, there are no/few effective therapies or biomarkers to treat or prevent MASLD. A better understanding of pathophysiological mechanisms represents a huge challenge for the discovery of new therapeutic targets.

Innate lymphoid cells (ILC) comprise a group of 5 cell populations, including natural killer (NK) cells and auxiliary ILC1, and represent one of the first line of defence of the organism. Numerous studies have highlighted the contribution of ILCs in the development of metabolic diseases (obesity, diabetes, MASLD) by regulating inflammation in target tissues: adipose tissue, liver, gut. In this context, we were interested in targeting NK cells/ILC1 during MASLD, as these cells are involved in the initiation and/or resolution of inflammatory, fibrotic and tumoral processes. We focused our attention on the surface glycoprotein CD44, known for its roles in cell interactions, adhesion, migration and activation. Our team has identified a key role for CD44 in the progression of MASH, enabling macrophages to acquire a pro-inflammatory phenotype. To better understand the role of NK cells/ILC1 and CD44 in the hepatic complications of obesity, we have generated a mouse model of specific CD44 invalidation within NK cells and ILC1 (NKp46+iCreCD44flox mice). Thus, the aims of my thesis were to evaluate: i) the impact of CD44-specific invalidation within NKp46+ ILCs on the development of MASLD and on NK cells/ILC1 dynamics in two dietary models inducing MASH/MASLD (choline and methionine-deficient diet, Western diet); ii) the impact of CD44-specific invalidation on NK cell and ILC1 functions; iii) the metabolism of CD44-invalidated NK cells. The results obtained revealed a correlation between the number of hepatic NK cells/ILC1 and hepatocyte suffering during MASH. In addition, the specific invalidation of CD44 within NK cells/ILC1 regulates their proportion, leading to a worsening of liver injury, inflammation and fibrosis. The severity of these lesions is notably associated with increased intestinal permeability. Activation of CD44-deficient hepatic NK cells by LPS induces an increase in their glycolytic capacity, the expression/secretion of inflammatory cytokines and also promotes the production of inflammatory mediators by hepatocytes. My thesis work suggests that CD44 is a regulator of some functions of hepatic NK cells, and its absence within these cells contributes to the development of the disease. Our study provides a better understanding of the pathophysiology of MALSD and suggests that targeting NK cell functions represents a line of investigation for the development of therapeutic approaches to prevent/treat obesity-associated liver complications.

Keywords : 

Innate Lymphoid Cells, NK cells, ILC1, liver, MASH, metabolism.