Abstract
Macrophages play central roles in inflammatory reactions and initiation of immune responses during infections. More than 80% of total tissue macrophages are described to be located in the liver as liver-resident macrophages, also named Kupffer cells (KCs). While studies in mice have established a central role of liver-resident KCs in regulating liver inflammation, their phenotype and function are not well-characterized in humans. Comparing paired human liver and peripheral blood samples, we observed significant differences in the distribution of macrophage (Mφ) subsets, with lower frequencies of CD14hiCD16lo and higher frequencies of CD14int−hiCD16int Mφ in human livers. Intrahepatic Mφ consisted of diverse subsets with differential expression of CD49a, a liver-residency marker previously described for human and mice NK cells, and VSIG4 and/or MARCO, two recently described human tissue Mφ markers. Furthermore, intrahepatic CD49a+ Mφ expressed significantly higher levels of maturation and activation markers, exhibited higher baseline levels of TNF-α, IL-12, and IL-10 production, but responded less to additional in vitro TLR stimulation. In contrast, intrahepatic CD49a− Mφ were highly responsive to stimulation with TLR ligands, similar to what was observed for CD49a− monocytes (MOs) in peripheral blood. Taken together, these studies identified populations of CD49a+, VSIG4+, and/or MARCO+ Mφ in human livers, and demonstrated that intrahepatic CD49a+ Mφ differed in phenotype and function from intrahepatic CD49a− Mφ as well as from peripheral blood-derived monocytes.
Highlights
Under homeostatic conditions, the liver represents an immuneprivileged and tolerogenic organ, reflected by a general lack of immune responses induced by foreign antigens [with some exceptions, such as schistosomiasis [1]], and low rates of liver allotransplantation rejections [2, 3]
Livers contain a large population of non-parenchymal immune cells, including hepatic stellate cells (HSC), dendritic cells (DCs), macrophages (Mφ), Natural Killer (NK) cells and liver sinusoidal endothelial cells (LSEC) [7]
While no differences were observed in the CD14loCD16hi subset between liver and peripheral blood (Figure 1A), the proportion of CD14int−hiCD16int cells was significantly upregulated and the proportion of CD14hiCD16lo cells downregulated in liverderived cells compared to peripheral blood (Figure 1A)
Summary
The liver represents an immuneprivileged and tolerogenic organ, reflected by a general lack of immune responses induced by foreign antigens [with some exceptions, such as schistosomiasis [1]], and low rates of liver allotransplantation rejections [2, 3]. The liver has been suggested to play a central role in the regulation of host immune defenses [4, 5], as both gastrointestinal portal and systemic blood circulations reach the liver, exposing liverresident immune cells to antigens [6]. Mφ and LSECs can absorb pathogens and molecules that entered the portal circulation after gastrointestinal translocation, as these cells are located within liver sinusoids, in close contact with the portal blood stream [8]. MOs have been defined as CD14hiCD16lo (classical), CD14int−hiCD16int (intermediate), or CD14loCD16hi (non-classical) monocytes [9], with distinct functional capacities. Mφ in liver have been suggested to have dual origins, as they have the capacity to self-renew or to differentiate from recruited infiltrating peripheral blood monocytes (MOs) [10]
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