Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response

Abstract

Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Engfl/flLysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Engfl/flLysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.

The role of endoglin in post-ischemic revascularization

“…This phenotype was rescued by the injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. This result is in agreement with the reduction in monocyte function (including oxidative burst and phagocytosis) in HHT patients [242] and in mouse monocytes lacking endoglin [243]. Moreover, a different role for endoglin isoforms in the regulation of monocyte-macrophage functions has been proposed because L-endoglin overexpression promotes a pro-inflammatory M1-like macrophage phenotype, whereas S-endoglin favors the expression of anti-inflammatory M2 macrophage markers [96].…”

Key Vitamin D Target Genes with Functions in the Immune System

“…ACVRL1 is a transmembrane protein of the transforming growth factor beta superfamily, which mediates the bone morphogenetic protein (BMP) 9-and BMP10-induced signaling that orchestrates the development of blood vessels [73]. This relates to the control of monocyte to macrophage differentiation [74]. SRGN is a secreted proteoglycan of endothelial cells, monocytes, mast cells and lymphocytes [75].…”

A novel association between high red blood cell alloimmunization rates and hereditary hemorrhagic telangiectasia

“…Furthermore, in a mouse model where ENG, one of genes involved in HHT, was conditionally deleted in myeloid lineage, it was found that 30% of conditional knockout mice developed spontaneous soft tissue abscesses. 18 Additional studies revealed impaired macrophage functions in these conditional knockout mice, including transmigration and phagocytosis. It is unclear how the HHT-associated macrophage defects might affect alloimmunization.…”

“…Cirulli and coworkers examined 20 patients with HHT and found that their neutrophils and monocytes were defective in oxidative burst and phagocytosis. Furthermore, in a mouse model where ENG, one of genes involved in HHT, was conditionally deleted in myeloid lineage, it was found that 30% of conditional knockout mice developed spontaneous soft tissue abscesses . Additional studies revealed impaired macrophage functions in these conditional knockout mice, including transmigration and phagocytosis.…”