Analysis of neutrophil-specific NLRP3 inflammasome activation in metabolic dysfunction-associated steatotic liver disease and liver regeneration

• Applicant: Dr. Benedikt Kaufmann
• Subject Area: General and Visceral Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566158747

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis and the leading primary cause of chronic liver disease worldwide today. Metabolic dysfunction-associated steatohepatitis (MASH), an inflammatory stage of MASLD, is characterized by steatosis and lobular inflammation. It represents a more severe course of the disease resulting in a higher risk of progressing to severe fibrosis, subsequently cirrhosis and hepatocellular carcinoma. The liver has a unique regenerative capacity to regain its size, architecture, and function in response to the loss of mass caused by a variety of injuries. Liver regeneration is defined by a well-organised and complex series of signals, which are generated by cytokines and growth factors. The regenerative capacity is often reduced when concomitant liver disease, such as liver fibrosis, cirrhosis or MASLD, is present. Besides liver function MASH also affects other organs system such as bone health. It is therefore important to decipher the molecular mediators that regulate liver regeneration In both MASH and liver regeneration/proliferation sterile inflammation is a central element as a response to liver injury. Interactions between immune and non-immune cells as well as recruited and resident cells mediate an inflammatory response that either results in restoration of liver homeostasis (liver regeneration) or its progression to chronic liver inflammation and fibrosis (MASH). In particular, neutrophils, the largest fraction of circulating leukocytes and known to initiate liver inflammation, have been identified as crucial mediators and shown to influence cellular function and phenotype. Neutrophils are the first responder immune cells that are rapidly recruited to the site of inflammation. Inflammasomes are intracellular multiprotein complexes that are key regulators of the innate immune response and are critical in defining outcomes of hepatic inflammation. The NLRP3 inflammasome has been implicated in sterile liver inflammation and induction of fibrosis. Intercellular crosstalk and signaling between hepatocytes, HSCs and immune cells is partly regulated by inflammasome activation. In this study we will analyse the microenvironment with new spatially resolved single-cell analysis and determine the role of NLRP3 expression in neutrophils in MASH and liver regeneration. We will generate a neutrophil-specific Nlrp3 knock-out mouse and induce MASH by a dietary model. In addition, partial hepatectomy will be performed to study NLRP3 expression in neutrophils during liver regeneration. Microenvironment in liver tissue, characteristics of neutrophils and affects on bone health will be analysed. The results of this study will give new insight in spatial cellular interaction particular NLRP3-dependent intercellular crosstalk and signaling after liver injury in MASH and liver regeneration.

• DFG Programme: Research Grants