Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris

Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as prom...

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Autores principales:	Aneese A. Jaffa, Miran A. Jaffa, Mayssam Moussa, Ibrahim A. Ahmed, Mia Karam, Kawthar Sharaf Aldeen, Rola Al Sayegh, Ghewa A. El-Achkar, Leila Nasrallah, Yara Yehya, Aida Habib, Fuad N. Ziyadeh, Ali H. Eid, Firas H. Kobeissy, Ayad A. Jaffa
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	neuroinflammation cytokines plasma kallikrein-kinin system protease-activated receptor 2 bradykinin 2 receptor interactome Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/8dd264650da5460bb2dfd713f8d2f363
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spelling	oai:doaj.org-article:8dd264650da5460bb2dfd713f8d2f3632021-11-17T16:05:59ZModulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris1663-981210.3389/fphar.2021.743059https://doaj.org/article/8dd264650da5460bb2dfd713f8d2f3632021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.743059/fullhttps://doaj.org/toc/1663-9812Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 μM), and neuronal cell debris (16.5 μg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 μM) and GB-83 (2 μM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.Aneese A. JaffaMiran A. JaffaMayssam MoussaIbrahim A. AhmedMia KaramKawthar Sharaf AldeenRola Al SayeghRola Al SayeghGhewa A. El-AchkarLeila NasrallahYara YehyaAida HabibAida HabibFuad N. ZiyadehFuad N. ZiyadehAli H. EidAli H. EidFiras H. KobeissyAyad A. JaffaFrontiers Media S.A.articleneuroinflammationcytokinesplasma kallikrein-kinin systemprotease-activated receptor 2bradykinin 2 receptorinteractomeTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neuroinflammation cytokines plasma kallikrein-kinin system protease-activated receptor 2 bradykinin 2 receptor interactome Therapeutics. Pharmacology RM1-950
spellingShingle	neuroinflammation cytokines plasma kallikrein-kinin system protease-activated receptor 2 bradykinin 2 receptor interactome Therapeutics. Pharmacology RM1-950 Aneese A. Jaffa Miran A. Jaffa Mayssam Moussa Ibrahim A. Ahmed Mia Karam Kawthar Sharaf Aldeen Rola Al Sayegh Rola Al Sayegh Ghewa A. El-Achkar Leila Nasrallah Yara Yehya Aida Habib Aida Habib Fuad N. Ziyadeh Fuad N. Ziyadeh Ali H. Eid Ali H. Eid Firas H. Kobeissy Ayad A. Jaffa Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
description	Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 μM), and neuronal cell debris (16.5 μg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 μM) and GB-83 (2 μM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.
format	article
author	Aneese A. Jaffa Miran A. Jaffa Mayssam Moussa Ibrahim A. Ahmed Mia Karam Kawthar Sharaf Aldeen Rola Al Sayegh Rola Al Sayegh Ghewa A. El-Achkar Leila Nasrallah Yara Yehya Aida Habib Aida Habib Fuad N. Ziyadeh Fuad N. Ziyadeh Ali H. Eid Ali H. Eid Firas H. Kobeissy Ayad A. Jaffa
author_facet	Aneese A. Jaffa Miran A. Jaffa Mayssam Moussa Ibrahim A. Ahmed Mia Karam Kawthar Sharaf Aldeen Rola Al Sayegh Rola Al Sayegh Ghewa A. El-Achkar Leila Nasrallah Yara Yehya Aida Habib Aida Habib Fuad N. Ziyadeh Fuad N. Ziyadeh Ali H. Eid Ali H. Eid Firas H. Kobeissy Ayad A. Jaffa
author_sort	Aneese A. Jaffa
title	Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
title_short	Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
title_full	Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
title_fullStr	Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
title_full_unstemmed	Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris
title_sort	modulation of neuro-inflammatory signals in microglia by plasma prekallikrein and neuronal cell debris
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8dd264650da5460bb2dfd713f8d2f363
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Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris

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