Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.

Prediction of severe hypertriglyceridemia-associated acute pancreatitis using a nomogram based on CT findings and blood biomarkers

“…[35] The activation of Kupffer cells by liver lipid infiltration leads to the expression of various inflammatory factors and simultaneously contributes to the inflammatory cascade. [36] In addition, a previous study reported that nonalcoholic fatty liver disease aggravates AP by increasing bacterial translocation in the liver and pancreas. [37] This finding may explain the reason for the association between the severity of HTG-AP and PCT in the present study, which is a sensitive indicator of bacterial infection.…”

Chronic Intermittent Hypoxia-Induced Dysmetabolism Is Associated with Hepatic Oxidative Stress, Mitochondrial Dysfunction and Inflammation

“…In agreement, we showed that CIH increased levels of F4/80 staining, a macrophage cell marker, in both control and HF diet animals, confirming the increased inflammation in these conditions. Knowing that F4/80 staining is high in Kupfer cells and in liver monocyte-derived macrophages (MoMFs) [54,55] and that the activation of these cells drives macrophage polarization and activation [56,57], it is plausible to conclude that CIH drives liver inflammation, contributing to hepatic and whole-body metabolic dysfunction.…”

From MASH to HCC: the role of Gas6/TAM receptors

“…In MASH, liver inflammation triggers the activation of KCs, as well as cells of the immune system that infiltrate the liver from the bloodstream, leading to fibrosis progression ( 104 ). KCs and monocyte-derived macrophages are indeed essential for the maintenance the immune function and serve as the first-line defense against pathogens.…”

“…In the context of liver inflammation, M1 macrophages contribute to hepatic steatosis, inflammatory cells recruitment and fibrosis activation, while M2 macrophages have anti-inflammatory and reparative functions. Thus, it has been demonstrated that M1/M2 ratio gradually increases during MASLD progression ( 104 , 105 ). After the development of hepatic steatosis, KCs secrete chemotactic substances facilitating the infiltration of monocytes.…”