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 ( Eng fl/fl LysMCre ) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Eng fl/fl LysMCre 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. Author Summary Endoglin is a transmembrane protein and an auxiliary receptor for TGF-β with an important role in the homeostasis of the vessel wall. However, endoglin was originally identified as a human cell surface antigen expressed in a pre-B leukemic cell line. Mutations in ENG are responsible for the Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) or Rendu-Osler-Weber syndrome. HHT is a rare disease, with a prevalence of 1/5,000 to 1/8,000. It is an autosomal dominant disorder characterized by a multisystemic vascular dysplasia, recurrent hemorrhages and arteriovenous malformations in internal organs. Interestingly, endoglin expression is also triggered during the monocyte-macrophage differentiation process. In our laboratory, we described that up-regulation of endoglin during in vitro differentiation of blood monocytes is age-dependent and impaired in monocytes from HHT patients, suggesting a role of endoglin in macrophages. In the present work, we first analyzed endoglin expression during differentiation of peripheral blood monocytes to macrophages under in vitro and in vivo conditions. Next, to investigate endoglin’s role in macrophage function in vivo , a myeloid-lineage specific endoglin knock-out mouse line was generated ( Eng fl/fl LysMCre ). Endoglin deficiency in macrophages predisposed animals to spontaneous infections and led to delayed endotoxin-induced mortality. Phagocytic activity by peritoneal macrophages was reduced in the absence of endoglin and altered expression of TGF-β target genes was consistent with an altered balance of TGF-β signaling. The results show a novel role for endoglin in mouse macrophages, which if analogous in human macrophages, may explain, at least in part, the increased infection rates seen in HHT patients.
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