Aberrant Activation of Myeloid Cells in Tissues is Driven by Dysregulated Endothelium in HHT

Objective Endothelium governs mobilization and activation of neutrophils and monocytes/macrophages, strongly influencing their functions in tissues. We hypothesized that in hereditary hemorrhagic teleangiectasia (HHT) defective function of endothelium leads to dysregulation of myeloid cells and impaired immune responses in HHT.

Methods In the mouse model with tamoxifen-inducible primary Acvrl1/ALK1- knockout in endothelial cells (Acvrl1fl/flCdh5-cre/ERT2tg), with genetically intact immune cells, the amount, phenotype and functions of lung neutrophils and macrophages were evaluated and compared with control animals (Acvrl1fl/flCdh5-cre/ERT2WT) 7 days after tamoxifen treatment. The analysis of open-access Gene Expression Omnibus datasets (human nasal mucosa) was performed to screen the changes in human tissues during HHT.

Results ALK1-deficient mice developed signs of anemia (hemodilution) and vascular shunting (volume overload, cardiomegaly). Such animals demonstrated the prominent lung infiltration with neutrophils, accompanied with the reduction of macrophages and dendritic cells (DCs) and dysregulation of myeloid cell activation: elevated NFkB1 in parallel with decreased interleukin (IL)-12 expression by neutrophils and macrophages/DCs. The analysis of gene expression in human nasal mucosa demonstrated the lower expression of IL-12a in intact tissues of HHT patients with pulmonary arteriovenous malformations (PAVM) as compared to patients without PAVM, suggesting the possible involvement of IL-12 in angiogenesis in HHT.

Conclusion In HHT we observed an aberrant activation of myeloid cells possibly influenced by endothelial cells. Moreover, the observed changes could lead to diminished antibacterial and immunostimulatory properties of myeloid cells in HHT.

Publication History

Article published online:
12 May 2023