Heterogeneity and Function of Kupffer Cells in Liver Injury

Abstract

Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.

TSH−SPP1/TRβ−TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver

“…Although certain extrahepatic sites, such as adipose tissue, have evolved as major sources of inflammatory mediators in obesity-related disorders, evidence is accumulating that intrahepatic inflammation might also be critically involved in the pathogenesis of NAFLD ( 39 , 40 ). Although multiple cell populations in the liver contribute to various inflammatory pathways, hepatic macrophages are considered key contributors to the process of metabolic inflammation that underlies the development of NAFLD ( 41 ). The functional heterogeneity of monocyte-derived macrophages was initially typified by their polarization into M1 and M2 phenotypes, which were thought to represent two ends of a spectrum in which M1 macrophages are proinflammatory and M2 macrophages are regenerative ( 42 ).…”

Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation

“…Recent studies have shown that non-parenchymal liver cells have important function in the tolerance induction following LT ( Knechtle and Kwun., 2009 ). Kupffer cells proved to have a dual performance in the pathological changes that occur after LT, Th1 cells correlated with rejection and Th2 predominance favoured graft acceptance and immunological tolerance ( Li et al, 2022 ).…”

Crosstalk between liver macrophages and gut microbiota: An important component of inflammation-associated liver diseases

“…Mature KCs share a series of common macrophage surface markers, such as CD11 and F4/80, whereas KCs in mice express the unique marker, C-type lectin domain family 4 member F (CLEC4F) ( Krenkel and Tacke, 2017 ; Li W. et al, 2022 ). These KCs usually inhabit liver sinusoids, where they continuously engage with and process senescent cells and various gut-derived particles.…”

“…Two main categories of macrophages are present in the liver: liver-resident Kupffer cells (KCs) and circulating monocyte-derived macrophages (MoMφs) ( Varol et al, 2015 ; Dou et al, 2019 ). In general, KCs are responsible for sensing and processing biochemical signals, such as pathogen components, cell fragments, and endo/exogenous metabolites ( Diehl et al, 2020 ; Li W. et al, 2022 ). They can trigger primary inflammation and secrete chemokines to recruit MoMφs for further inflammatory responses ( Wen et al, 2021 ; Zhou J. et al, 2022 ).…”

“…Hepatic macrophages can also regulate inflammatory responses when stimulated with anti-inflammatory factors. Hence, the signaling pathways associated with macrophage activity and heterogeneity induced by different agents play a vital role in inflammation-associated liver diseases ( Dou et al, 2019 ; Wen et al, 2021 ; Li W. et al, 2022 ).…”