Altered levels of phospholipases C, diacylglycerols, endocannabinoids, and N-acylethanolamines in patients with hereditary angioedema due to FXII mutation.

Francesco Palestra, Anne Lise Ferrara, Alberto López-Lera, Davide Firinu, Teresa Caballero, Angelica Petraroli, Gianni Marone, Fabiana Piscitelli, Stefania Loffredo, Giuseppe Spadaro, Vincenzo Di Marzo, Chiara Suffritti, Konrad Bork, Maria Bova

Journal: Allergy 2025;80(1):287-296

PMID: 38935036

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Abstract

BACKGROUND

Hereditary angioedema (HAE) is a rare genetic disorder characterized by local, self-limiting edema due to temporary increase in vascular permeability. HAE with normal C1 esterase inhibitor (C1INH) activity includes the form with mutations in the F12 gene encoding for coagulation factor XII (FXII-HAE) causing an overproduction of bradykinin (BK) leading to angioedema attack. BK binding to B2 receptors (BK2R) leads to an activation of phospholipase C (PLC) and subsequent generation of second messengers: diacylglycerols (DAGs) and possibly the endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and eCB-related N-acylethanolamines [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)]. To date, there are no data on the role of these lipid mediators in FXII-HAE.

METHODS

Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals.

RESULTS

Plasma PLC activity was increased in FXII-HAE patients compared to controls. Concentrations of DAG 18:1-20:4, a lipid second messenger produced by PLC, were higher in FXII-HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2-AG were altered in FXII-HAE. AEA and OEA were decreased in FXII-HAE patients compared to controls; by contrast, PEA, was increased. The levels of all tested mediators did not differ between symptomatic and asymptomatic patients. Moreover, C1INH-HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls.

CONCLUSIONS

BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII-HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII-HAE, and provide new potential biomarkers and therapeutic targets.

Address: Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, WAO Center of Excellence, Naples, Italy.; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare-Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.; Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, WAO Center of Excellence, Naples, Italy.; Italian Network for Hereditary and Acquired Angioedema, Napoli, Italy.; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.; Italian Network for Hereditary and Acquired Angioedema, Napoli, Italy.; Internal Medicine, Allergy and Clinical Immunology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.; Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754), Madrid, Spain.; Allergy Department, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754), Madrid, Spain.; Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.; Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, WAO Center of Excellence, Naples, Italy.; Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy.; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare-Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Quèbec, and Centre NUTRISS, Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec City, Canada.; Department of Internal Medicine, A.O.R.N. Antonio Cardarelli, Naples, Italy.; Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, WAO Center of Excellence, Naples, Italy.; Italian Network for Hereditary and Acquired Angioedema, Napoli, Italy.; Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy.

DOI: 10.1111/all.16197

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MeSH Terms: Humans, Male, Female, Mutation, Endocannabinoids, Adult, Ethanolamines, Factor XII, Middle Aged, Angioedemas, Hereditary, Type C Phospholipases, Young Adult, Case-Control Studies