The Adhesion GPCR ADGRL2/LPHN2 Can Protect Against Cellular and Organismal Dysfunction
Philipp Jakobs,
Anne Rafflenbeul,
Willem Berend Post,
Niloofar Ale-Agha,
Victoria Elisabeth Groß,
Stephanie Pick,
Sascha Dolata,
Fiona F. Cox,
Florian von Ameln,
Olaf Eckermann,
Joachim Altschmied,
Simone Prömel,
Judith Haendeler
Affiliations
Philipp Jakobs
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Anne Rafflenbeul
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Willem Berend Post
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Niloofar Ale-Agha
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Victoria Elisabeth Groß
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Stephanie Pick
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Sascha Dolata
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Fiona F. Cox
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Florian von Ameln
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Olaf Eckermann
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Joachim Altschmied
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Simone Prömel
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Judith Haendeler
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
The most common trigger of sepsis and septic shock is bacterial lipopolysaccharide (LPS). Endothelial cells are among the first to encounter LPS directly. Generally, their function is closely linked to active endothelial NO Synthase (eNOS), which is significantly reduced under septic conditions. LPS treatment of endothelial cells leads to their activation and apoptosis, resulting in loss of integrity and vascular leakage, a hallmark of septic shock. Hence, therapies that prevent endothelial leakage or restore the endothelial barrier would be invaluable for patients. Adhesion GPCRs (aGPCRs) have been largely overlooked in this context, although particularly one of them, ADGRL2/LPHN2, has been implicated in endothelial barrier function. Our study shows that overexpression of ADGRL2 protects endothelial cells from LPS-induced activation, apoptosis, and impaired migration. Mechanistically, ADGRL2 preserves eNOS activity by shifting its binding from Caveolin-1 to Heat Shock Protein 90. Furthermore, ADGRL2 enhances antioxidative responses by increasing NRF2 activity. Notably, we found that this function may be evolutionarily conserved. In the absence of lat-2, a homolog of ADGRL2 in Caenorhabditis elegans, worms show higher ROS levels and altered stress response gene expression. Additionally, lat-2 mutants have a significantly reduced lifespan, altogether indicating a protective role of ADGRL2 against oxidative stress across species.
