Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation

Abstract

Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

“…Inflammation is the main reason for the pathogenesis of NASH [24,25]. Quantitative real-time PCR and Western blot analysis showed that the combination of blueberry juice and probiotic bacteria had a significant inhibitory effect on inflammatory cytokines IL-6 and TNF-α.…”

“…Some data suggested that NASH patients could receive antioxidant therapies according to the oxidative stresses in their serum [23]. Inflammation is another important factor causing NASH because NASH is mainly characterized by hepatic lipid accumulation and is associated with progressive inflammatory liver disease [24,25]. The liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid and complications are associated with inflammation in animal NASH models [26].…”

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

“…The recruitment of bone marrow‐derived monocytes has been shown to be a critical event in the progression of NASH. KC‐derived factors facilitate a substantial infiltration of these monocytes into the liver, where together with KCs they contribute to the triggering and progression of disease through their inflammatory functions . In mouse models of NASH, inhibition of CCL2 or CCL2 receptor (CCR2) leads to reduced recruitment of monocyte‐derived macrophages, improved IR, hepatic inflammation, and fibrosis .…”

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

“…In the initial phase of NAFLD, resident immune cells such as KCs and dendritic cells respond to early signs of hepatocellular damage by generating plentiful proinflammatory cytokines like IL-1 β and chemokines like chemokine ligand 2 (CCL2), which further promote inflammatory cell infiltration, thus leading to a vicious cycle [64, 68]. It was reported recently that early depletion of KCs using liposomal clodronate could block the development of NASH [69]. In addition, several mediators have been demonstrated which play a positive role in regulating inflammation in the context of NAFLD.…”