1. Academic Validation
  2. Non-functional TGF-β/ALK1/ENG Signaling Pathway supports neutrophil pro-angiogenic activity in Hereditary Hemorrhagic Telangiectasia

Non-functional TGF-β/ALK1/ENG Signaling Pathway supports neutrophil pro-angiogenic activity in Hereditary Hemorrhagic Telangiectasia

  • J Leukoc Biol. 2023 Aug 9;qiad090. doi: 10.1093/jleuko/qiad090.
Inga Duerig 1 Ekaterina Pylaeva 1 Irem Ozel 1 Sami Weinwright 1 Ilona Thiel 1 Sharareh Bordbari 1 Maksim Domnich 1 Elena Siakaeva 1 Antonia Lakomek 2 Felicia Toppe 2 Carolin Schleupner 2 Urban Geisthoff 3 Stephan Lang 2 4 Freya Droege 2 Jadwiga Jablonska 1 4
Affiliations

Affiliations

  • 1 Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Germany.
  • 2 VASCERN HHT Reference Centre and Department Department of Otorhinolaryngology, Head and Neck Surgery, Essen University Hospital, University Duisburg-Essen, Germany.
  • 3 VASCERN HHT Reference Centre and Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Marburg, University of Gießen and Marburg, Germany.
  • 4 German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany.
Abstract

TGF-β/ALK1/ENG signaling pathway maintains quiescent state of endothelial cells, but at the same time, it regulates neutrophil functions. Importantly, mutations of this pathway lead to a rare autosomal disorder called Hereditary Hemorrhagic Telangiectasia (HHT), characterized with abnormal blood vessel formation (angiogenesis). As neutrophils are potent regulators of angiogenesis, we investigated how disturbed TGF-β/ALK1/ENG signaling influences angiogenic properties of these cells in HHT. We could show for the first time that not only endothelial cells, but also neutrophils isolated from such patients are ENG/ALK1-deficient. This deficiency obviously stimulates proangiogenic switch of such neutrophils. Elevated proangiogenic activity of HHT neutrophils is mediated by the increased spontaneous degranulation of gelatinase granules, resulting in high release of matrix-degrading MMP9. In agreement, therapeutic disturbance of this process using Src tyrosine kinase inhibitors impaired proangiogenic capacity of such neutrophils. Similarly, inhibition of MMP9 activity resulted in significant impairment of neutrophil-mediated angiogenesis. All in all, deficiency in TGF-β/ALK1/ENG signaling in HHT neutrophils results in their proangiogenic activation and disease progression. Therapeutic strategies targeting neutrophil degranulation and MMP9 release and activity may serve as a potential therapeutic option for HHT.

Keywords

ALK1; ENG; HHT; MMP9; angiogenesis; neutrophils.

Figures
Products