A conserved pathway of transdifferentiation in murine Kupffer cells

Abstract

Abundant long‐lived liver‐resident macrophages, termed Kupffer cells, are activated during chronic liver injury. They secrete both pro‐inflammatory and pro‐fibrotic cytokines, which act on hepatic stellate cells causing their transdifferentiation into myofibroblasts that deposit collagen. In other tissues, wound‐associated macrophages go further, and transdifferentiate into fibrocytes, secreting collagen themselves. We tested Kupffer cells for this property in two experimental models: mixed non‐parenchymal cell culture, and precision‐cut liver slice culture. Using the Emr1‐Cre transgene as a driver and the RiboTag transgene as a reporter, we found that Kupffer cells undergo transdifferentiation under these circumstances. Over time, they lose the expression of both Kupffer cell‐specific and macrophage‐specific genes and the transcription factors that control their expression, and they begin to express multiple genes and proteins characteristic of either myofibroblasts or tissue fibroblasts. These effects were strongly conserved between non‐parenchymal cell culture and liver tissue slice culture, arguing that such transdifferentiation is a conserved function of Kupffer cells. We conclude that in addition to supporting fibrosis through an action on stellate cells, Kupffer cells also participate in liver fibrosis through transdifferentiation into fibrocytes.

FADD- and RIPK3-mediated cell death ensures timely clearance of wound macrophages and promotes wound healing

“…The current view is that in most repairing tissues, including the skin, inflammatory monocytes/macrophages (Ly6C high ) undergo a phenotypic switch from a pro-inflammatory towards an anti-inflammatory phenotype (Willenborg, 2012; Knipper, 2015; Willenborg, 2021; Sanin, 2022). In addition, monocytic cells can be cleared through lymphatic drainage (Harmsen, 1985; Bellingan, 1996), recently described trans-differentiation (Meng, 2016; Sinha, 2018; Haider, 2019; Li, 2021), and/or cell death (Desmoulière, 1995; Kuhlmann, 2001; Janssen, 2011; Gautier, 2013; Moriwaki, 2014; Wu, 2014; Bleriot, 2015; Legrand, 2019). However, the contribution and the dynamics of these different resolution mechanisms, particularly also the role of different cell death modalities in the removal of inflammatory macrophages in inflamed tissues remains elusive.…”

“…In addition to the requirement to sense and respond rapidly to distinct damage signals, macrophages need to be cleared from the wound site at later time points in order to govern the return to tissue homeostasis (Eming, 2014; Knuever, 2015; Eming, 2017; Do, 2018). The dominant fate of injury-associated monocytes/macrophages at the wound site during resolution of inflammation is unclear and under debate (Majka, 2010; Sinha, 2018, Li, 2021). Recent evidence, particularly in tissues other than skin, suggests a critical role of different forms of myeloid cell death in tissue homeostasis and repair (Moriwaki, 2014; Bleriot, 2015).…”

Production of a p65fl/fl/LysMCre mouse model with dysfunctional NF-κB signaling in bone marrow-derived macrophages

“…The liver has a large population of resident macrophages called Kupffer cells, even during times of health. 29 As most Kupffer cells are also yolk sac-derived 30,31 and not bone-marrow derived, we did not anticipate p-p65/p65 differences, which was supported by the western data (Figure 2c).…”

Triptolide Induces Liver Injury by Regulating Macrophage Recruitment and Polarization via the Nrf2 Signaling Pathway

“…KCs maintain liver homeostasis through the clearance of pathogenic microbes and phagocytosis of cellular debris. MoMFs infiltrate into the liver tissues when cellular damage occurs and have potent cytokine-producing capacities [ 35 , 36 ]. Macrophages undergo polarized activation to M1- or M2-like phenotypic states by adapting to the local microenvironment during the progression of liver injury.…”