Dataset Information

CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

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 (M?) subsets, with lower frequencies of CD14^hiCD16^lo and higher frequencies of CD14^int-hiCD16^int M? in human livers. Intrahepatic M? 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 M? markers. Furthermore, intrahepatic CD49a⁺ M? expressed significantly higher levels of maturation and activation markers, exhibited higher baseline levels of TNF-?, IL-12, and IL-10 production, but responded less to additional in vitro TLR stimulation. In contrast, intrahepatic CD49a^- M? 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⁺ M? in human livers, and demonstrated that intrahepatic CD49a⁺ M? differed in phenotype and function from intrahepatic CD49a^- M? as well as from peripheral blood-derived monocytes.

SUBMITTER: Martrus G

PROVIDER: S-EPMC6568245 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

Martrus Glòria G Goebels Hanna H Langeneckert Annika E AE Kah Janine J Flomm Felix F Ziegler Annerose E AE Niehrs Annika A Löbl Sebastian M SM Russu Kristina K Hess Leonard U LU Salzberger Wilhelm W Poch Tobias T Nashan Björn B Schramm Christoph C Oldhafer Karl J KJ Dandri Maura M Koch Martina M Lunemann Sebastian S Altfeld Marcus M

Frontiers in immunology 20190607

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 obse ...[more]

PMID: 31231382

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Project description:In autoimmune diseases, toll-like receptor (TLR)-stimulated pro-inflammatory IL-6-secreting B cells exert pathogenic roles. Similarly, B cell Fc receptor-like 4 (FcRL4) expression amplifies TLR stimulation, and in rheumatoid arthritis patients, FcRL4 expression identifies a pro-inflammatory B cell subset. B cells from HIV-infected subjects also express heightened levels of FcRL4 and secrete high levels of IL-6: a critical mediator of HIV disease progression. In this study, we sought to determine if FcRL4 identifies a pro-inflammatory B cell subset in HIV-infected subjects and further elucidate the mechanisms underlying FcRL4 amplification of TLR stimulation. We determine that tissue-like memory B cells express the highest endogenous levels of FcRL4 positively correlating with IL-6 expression (p?=?0.0022, r?=?0.8667), but activated memory B cells exhibit the highest frequency of FcRL4hiIL-6hi cells. FcRL4hi B cells exhibit an activated TLR-signaling pathway identified by elevated phosphorylation levels of: pERK (p?=?0.0373), p38 (p?=?0.0337), p65 (p?=?0.1097), and cJUN (p?=?0.0239), concomitant with significantly elevated expression of the TLR-signaling modulator hematopoietic cell kinase (HcK, p?=?0.0414). Compared to FcRL4neg B cells from healthy controls, TLR9-stimulated FcRL4pos B cells express significantly higher levels of lL-6 (p?=?0.0179). Further, TLR9-stimulated B cells also upregulate the expression of FcRL4 (p?=?0.0415) and HcK (p?=?0.0386). In B-cell lines, siRNA-mediated HcK knockdown downmodulates TLR9-induced FcRL4-mediated activation quantified by CD23 upregulation (p?=?0.0553). We present data suggesting that, in viremic HIV-infected individuals, FcRL4 expression identifies unique IL-6 producing pro-inflammatory B-cell subsets. Further, TLR stimulation likely modulates FcRL4 expression and FcRL4 expression is associated with Hck, potentially enhancing the activation of TLR-signaling associated transcription factors. Pathogenic B-cells have been identified in other disease settings, and this study represents a novel report describing a pro-inflammatory B cell subset in HIV-infected patients.

Dataset Information

CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

Publications

CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

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