CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans

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 CD14^hiCD16^lo and higher frequencies of CD14^int-hiCD16^int 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.