Pivotal roles of Kupffer cells in the progression and regression of DDC-induced chronic cholangiopathy

Abstract

Kupffer cells (KCs) are key players in maintaining tissue homeostasis and are involved in various liver diseases. However, the roles of KCs in the pathogenesis of cholangiopathy are largely unknown. We aimed to investigate the precise roles of KCs in both the progression and regression phases of the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy model. In the early phase of DDC-induced cholangiopathy, the number of KCs significantly increased over time. Moreover, KCs were associated with abnormal phenotypic changes in other liver cells, such as hepatocytes, biliary epithelial cells, liver sinusoidal endothelial cells, and hepatic stellate cells. In contrast, KC depletion by clodronate administration suppressed the progression of the disease, and maintained the phenotypes of other cells. In the regression phase, the numbers of KCs significantly decreased, and the cells redifferentiated to their quiescent state. In contrast, KC depletion delayed the recovery of cells by maintaining other liver cells in an active state. These findings suggest that KCs play detrimental roles in the progression phase; however, they are beneficial in the regression phase by mediating interactions between other liver cells. Our data provide new insights into the roles of KCs in the pathogenesis of cholangiopathy.

Dysregulation of intercellular signaling by MOF deletion leads to liver injury

“…These signaling pathways have been reported as the major contributors to NASH progression in patients ( 43 ). The activated macrophages, in turn, release NO and other cytokines to induce apoptosis as well as proinflammatory responses in the liver as previously reported ( 44 , 45 ). In the feedback loop, Mof deletion in hepatocytes also enhances sensitivity to NO-mediated death signaling ( Fig.…”

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Figure 4 MOF and MOF-dependent gene network are dysregulated in human NASH patients. A , FPKM expression values of MOF in human NASH patients and healthy controls (∗ p < 0.05, student t -test) (GSE134422) ( 45 ). B , Venn diagram of differentially expressed genes (fold change > 2) in M of null mouse livers and human NASH samples.

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Oxygen and Conformation Dependent Protein Oxidation and Aggregation by Porphyrins in Hepatocytes and Light-Exposed Cells

“…Several contexts might promote light-independent generation of oxidative stress (Figure 15). For example, after DDC feeding there is an influx of inflammatory cells,69, 70 with subsequent ROS generation including hypochlorous acid (from myeloperoxidase), O 2 - (from reduced nicotinamide adenine dinucleotide phosphate oxidase), and peroxynitrite (from nitric oxide synthase) that could provide the second oxidative hit and lead to protein oxidation and then formation of protein–porphyrin aggregates. In addition to inflammatory triggers, porphyrin accumulation might cause light-independent ROS by interacting with the hepatic cytochrome P450 system.…”

Understanding the Biology of Self-Renewing Macrophages

“…Kupffer cell number is restored to its initial level after Kupffer cell depletion [ 29 , 30 ]. Also, a high Kupffer cell number increases patient survival rates following liver transplantation [ 31 ], and alterations in Kupffer cell number are associated with specific liver pathologies [ 32 ], although distinguishing bona fide Kupffer cells from infiltrating monocytes and monocyte-derived macrophages is challenging. Akin to other macrophage populations, Kupffer cells were long believed to lack the ability to proliferate [ 33 ], and monocytes were thought to be their sole source for replenishment [ 34 ].…”