Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients

Growing evidence shows that the immune system is critically involved in Alzheimer’s disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannab...

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Main Authors: Valerio Chiurchiù, Lucia Scipioni, Beatrice Arosio, Daniela Mari, Sergio Oddi, Mauro Maccarrone
Format: Article
Language:English
Published: MDPI AG 2021-03-01
Series:Biomolecules
Subjects:
Online Access:https://www.mdpi.com/2218-273X/11/4/502
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author Valerio Chiurchiù
Lucia Scipioni
Beatrice Arosio
Daniela Mari
Sergio Oddi
Mauro Maccarrone
author_facet Valerio Chiurchiù
Lucia Scipioni
Beatrice Arosio
Daniela Mari
Sergio Oddi
Mauro Maccarrone
author_sort Valerio Chiurchiù
collection DOAJ
description Growing evidence shows that the immune system is critically involved in Alzheimer’s disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannabinoid (eCB) system in modulating immune functions, we investigated the potential role of the main elements of such a system, namely type-1 and type-2 cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>), and fatty acid amide hydrolase (FAAH), in distinct immune cell populations of the peripheral blood of AD patients. We found that, compared to healthy controls, CB<sub>1</sub> and CB<sub>2</sub> expression was significantly lower in the B-lymphocytes of AD patients. Moreover, we found that CB<sub>2</sub> was significantly lower and FAAH was significantly higher in monocytes of the same subjects. In contrast, T-lymphocytes and NK cells did not show any variation in any of these proteins. Of note, monocytic CB<sub>2</sub> and FAAH levels significantly correlated with clinical scores. Furthermore, the pharmacological inactivation of FAAH in monocytes and monocyte-derived macrophages obtained from AD patients was able to modulate their immune responses, by reducing production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12, and enhancing that of the anti-inflammatory cytokine IL-10. Furthermore, FAAH blockade skewed AD monocyte-derived macrophages towards a more anti-inflammatory and pro-resolving phenotype. Collectively, our findings highlight a central role of FAAH in regulating AD monocytes/macrophages that could be of value in developing novel monocyte-centered therapeutic approaches aimed at promoting a neuroprotective environment.
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spelling doaj.art-89b814bcc8ed4935903b355fc9e81eba2023-11-21T12:58:58ZengMDPI AGBiomolecules2218-273X2021-03-0111450210.3390/biom11040502Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease PatientsValerio Chiurchiù0Lucia Scipioni1Beatrice Arosio2Daniela Mari3Sergio Oddi4Mauro Maccarrone5Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, ItalyLaboratory of Neurochemistry of Lipids, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, 00143 Rome, ItalyGeriatric Unit, Fondazione Ca’ Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, ItalyGeriatric Unit, Fondazione Ca’ Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, ItalyLaboratory of Neurochemistry of Lipids, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, 00143 Rome, ItalyLaboratory of Neurochemistry of Lipids, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, 00143 Rome, ItalyGrowing evidence shows that the immune system is critically involved in Alzheimer’s disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannabinoid (eCB) system in modulating immune functions, we investigated the potential role of the main elements of such a system, namely type-1 and type-2 cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>), and fatty acid amide hydrolase (FAAH), in distinct immune cell populations of the peripheral blood of AD patients. We found that, compared to healthy controls, CB<sub>1</sub> and CB<sub>2</sub> expression was significantly lower in the B-lymphocytes of AD patients. Moreover, we found that CB<sub>2</sub> was significantly lower and FAAH was significantly higher in monocytes of the same subjects. In contrast, T-lymphocytes and NK cells did not show any variation in any of these proteins. Of note, monocytic CB<sub>2</sub> and FAAH levels significantly correlated with clinical scores. Furthermore, the pharmacological inactivation of FAAH in monocytes and monocyte-derived macrophages obtained from AD patients was able to modulate their immune responses, by reducing production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12, and enhancing that of the anti-inflammatory cytokine IL-10. Furthermore, FAAH blockade skewed AD monocyte-derived macrophages towards a more anti-inflammatory and pro-resolving phenotype. Collectively, our findings highlight a central role of FAAH in regulating AD monocytes/macrophages that could be of value in developing novel monocyte-centered therapeutic approaches aimed at promoting a neuroprotective environment.https://www.mdpi.com/2218-273X/11/4/502Alzheimer’s diseasecytokinesfatty acid amide hydrolaseimmunomodulationmonocytes/macrophages
spellingShingle Valerio Chiurchiù
Lucia Scipioni
Beatrice Arosio
Daniela Mari
Sergio Oddi
Mauro Maccarrone
Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
Biomolecules
Alzheimer’s disease
cytokines
fatty acid amide hydrolase
immunomodulation
monocytes/macrophages
title Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
title_full Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
title_fullStr Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
title_full_unstemmed Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
title_short Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer’s Disease Patients
title_sort anti inflammatory effects of fatty acid amide hydrolase inhibition in monocytes macrophages from alzheimer s disease patients
topic Alzheimer’s disease
cytokines
fatty acid amide hydrolase
immunomodulation
monocytes/macrophages
url https://www.mdpi.com/2218-273X/11/4/502
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