PD-L1+ Neutrophils mediate Susceptibility during Systemic Inflammatory Response in Non-Alcoholic Fatty Liver Disease
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Non-alcoholic fatty liver disease (NAFLD) is a pathological condition affecting individuals worldwide. Patients with NAFLD are more susceptible to systemic inflammation, such as sepsis, which accelerates liver damage. However, the immunological mechanisms that trigger the hyper-inflammatory responses in individuals with NAFLD remain unknown. In the present study, we reported that short-term HFCD (Choline Deficient High Fat Diet)-fed mice, which did not show significative signs of hepatic damage and inflammation in the first two weeks, are more susceptible to mortality after lipopolysaccharide (LPS) challenge. Mechanistically, endotoxemic mice show an excessive accumulation of NK-producing IFN-γ cells in liver tissue triggering the recruitment and polarization of a distinct neutrophil subset, characterized by high PD-L1 expression and massive TNFα production. Remarkably, genetic inhibition of IFN-γ or pharmacological blockade of PD-L1 effectively modulated the excessive recruitment of these neutrophils to the liver and TNFα release, thereby preventing hepatic damage and reducing the severity of host mortality. Thus, these results support the design of novel effective strategies to control hyperinflammatory responses in patients with HFCDs and consequently prevent hepatic damage and mortality..