Abstract
The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.
Highlights
In case of Kupffer cell death or depletion, as it occurs in acute liver injury, circulating monocytes can contribute to the Kupffer cell pool as well [16] (Figure 1)
In line with the notion of macrophage heterogeneity in nonalcoholic steatohepatitis (NASH) models, another comprehensive study applying unbiased single cell transcriptome analysis in mice revealed and confirmed: (i) resident Kupffer cells are gradually lost and replaced by monocytederived Kupffer cells during disease progression; (ii) resident Kupffer cells are not proinflammatory, suggesting that inflammatory phenotypes in previous studies might have been associated with infiltrating rather than resident Kupffer cells; (iii) infiltrating monocytes differentiated into another C-type lectin domain family 4 member F (CLEC4F)− osteopontin-expressing macrophage subpopulation with a transcriptomic profile similar to lipid associated macrophages (LAMs) [99]
DAMPS and pathogen-associated molecular patterns (PAMPs) released upon liver injury immediately trigger local Kupffer cells to alarm and recruit monocytes from the blood stream into the tissue to support the inflammatory situation
Summary
Apart from its central role as a metabolic organ, the liver is of critical importance for immune homeostasis and immunological responses to injury It is located at an intersection of systemic circulation receiving arterial blood through the hepatic artery and portal venous gut-derived blood, enriched with nutrients and microbial products. Inflammatory mediators are released by activated and stressed cells while the number of dead cells increases These microenvironmental changes have a tremendous impact on the phenotypes of Kupffer cells and monocyte-derived macrophages. Their phenotypes determine the functional contribution of macrophages to tissue restoration or aggravation of liver injury [9,10,11]. We will discuss potential implications for ameliorating liver injury in the clinical setting
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