Abstract
Simple SummaryIn the present study, we provide a detailed characterization of Lilrb4 expression in microglia and peripheral myeloid cells. Our data demonstrate that LILRB4 is a marker for microglia activation, as evidenced by upregulation after lipopolysaccharide treatment and inhibition of microglial TGFβ signaling. Moreover, we provide evidence that microglia express low levels of Lilrb4 in vivo and high levels in vitro, and we clearly demonstrate that LILRB4 is also expressed by bone marrow-derived monocytes and, to a greater extent, by peritoneal macrophages, defining LILRB4 as a surface marker of myeloid cells and not as a microglia-specific marker.As resident innate immune cells of the CNS, microglia play important essential roles during physiological and pathological situations. Recent reports have described the expression of Lilrb4 in disease-associated and aged microglia. Here, we characterized the expression of Lilrb4 in microglia in vitro and in vivo in comparison with bone marrow-derived monocytes and peritoneal macrophages in mice. Using BV2 cells, primary microglia cultures as well as ex vivo isolated microglia and myeloid cells in combination with qPCR and flow cytometry, we were able to provide a comprehensive characterization of Lilrb4 expression in distinct mouse myeloid cells. Whereas microglia in vivo display low expression of Lilrb4, primary microglia cultures present high levels of surface LILRB4. Among the analyzed peripheral myeloid cells, peritoneal macrophages showed the highest expression levels of Lilrb4. Moreover, LPS treatment and inhibition of microglial TGFβ signaling resulted in significant increases of LILRB4 cell surface levels. Taken together, our data indicate that LILRB4 is a reliable surface marker for activated microglia and further demonstrate that microglial TGFβ signaling is involved in the regulation of Lilrb4 expression during LPS-induced microglia activation.
Highlights
Microglia are specialized resident innate immune cells which mediate immune surveillance of the central nervous system (CNS) and play important roles under physiological and pathological conditions [1,2]
We provide a comprehensive characterization of LILRB4 expression in mouse microglia in vitro and in vivo in comparison with peritoneal macrophages and bone marrow-derived monocytes
NMRI mice used for establishment of primary microglia cultures as well as for the isolation of peritoneal macrophages and bone marrow-derived monocytes at indicated postnatal stages were purchased from Janvier (Le Genest-Saint-Isle, France)
Summary
Microglia are specialized resident innate immune cells which mediate immune surveillance of the central nervous system (CNS) and play important roles under physiological and pathological conditions [1,2]. PU. and IRF8 are necessary for primitive macrophages to arise from the yolk sac [3,4]. Prior to birth, these microglia precursor cells actively migrate toward the developing CNS in dependence of the interleukin-34 (IL-34) and colony-stimulating factor 1 receptor (CSF1R) ligand-receptor axis [5,6]. Within the first postnatal weeks, microglia mature and start to establish a unique and cell-specific gene expression signature that clearly distinguishes these resident CNS immune cells from other macrophage populations and is characterized by the increased expression of genes such as transmembrane protein 119 (Tmem119), purinergic receptor P2Y12. Olfml have been described to be direct TGFβ1-Smad target genes, and recent studies have confirmed that the microglia maturation process is dependent on neural TGFβ1, microglial TGFβ signaling, and proper extracellular TGFβ1 processing and binding [9,11,12,13].
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