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A new paradigm to study NF-κB in vivo and the role of dietary phenolic metabolites using drosophila / Sara Isabel Guerreiro Mota ; orient. Rita O. Teodoro

Main Author Mota, Sara Isabel Guerreiro Secondary Author Teodoro, Rita Language Inglês. Country Portugal. Publication Lisboa : NOVA Medical School, 2022 Abstract Neuroinflammation is a common feature of neurodegenerative diseases. Although it is still not consensual if itrepresents the cause or consequence of the development of suchpathologies, it is established that sustained pro-inflammatory glial responses can induce collateral damage in the host’s nervous system. In fact, glial hyperactivation of innate immune pathways, such as Nuclear Factor kappa-B (NF-κB), can impair neuronal activity and promote neuronal loss, leading tolong-term neurological impairments. Thus, the development of strategies to study and modulate glial NF-κB could enable the discovery of plausible therapeutic approaches to balance inflammation in the right direction, mitigating its deleterious effects. Akin to mammals, in Drosophilamelanogasterthe hyperactivation of NF-κB-like proteins, such as Relish, in glial cells has been demonstrated to cause neurodegeneration. Even though great progress has been made in thistopic,many aspects regarding inflammation-driven neuronal loss as well as the ability of Drosophilaglial cells to be immune responsive remain unclear andill-definedRecently, Low molecular weight (poly)phenols metabolites (LMWPM), which originated from fruit and vegetable human metabolism, such as Pyrogallol-sulfate, arose as promising candidates to control neuroinflammation, due to their described in vitroabilities to decreaseneuroinflammatory markersand their pleiotropic and positive effects in several mammalian and invertebrate neurodegenerative models. Therefore, we aimed to understand the immune responsive ability of fruit flies’glial cells andto develop a method in which we could study the anti-neuroinflammatory ability of LMWPM.In this study, we establisheda new paradigm to study in vivoNF-κB activation inDrosophila,in a neuroinflammatory context. We use a fused Relish-YFP proteintransgeneto track its activation upon exposure to gram-bacteria peptidoglycan, an inflammatory molecule known to activate Relish.Here, we identify,amongst the glial cells present in the peripheral nervous system, subperineurial and wrapping glia as immune responders and perineurial glia as non-responsive. Furthermore, we tested if our model was sensible to already known NF-κB inhibitors(such as Aspirin)andstudied the anti-neuroinflammatory potential of Pyrogallol-sulfate. We show thatAspirinpreventsPGN-dependent activation of Relish in glial cells. Moreover, we are the first to show that Pyrogallol-sulfatehas anti-neuroinflammatory propertiesin a multicellular organism, since we observe that it inhibits Relish PGN-dependent activation in glial cellsin 3rdinstar Drosophilalarvae. In summary, our findings provide a new in vivoneuroinflammatory model to dissect the molecular and cellular mechanisms behind neuroinflammation in Drosophila, filling the gaps regarding the way the fruit flies’ nervous system responds to inflammatory molecules. Additionally, our new method demonstrates the potential of Drosophilafor the versatile and fast screening of potential anti-neuroinflammatory compounds, paving the way for the discovery of plausible new therapeutics for controlling neuroinflammation and mitigating the impactof neurodegenerative diseases. Topical name Drosophila
Neuroinflammation
Relish
Low molecular weight Polyphenol metabolites
Academic Dissertations
Index terms Dissertação de Mestrado
Investigação Biomédica
NOVA Medical School
Universidade NOVA de Lisboa
2022
Online Resources Click here to access the eletronic resource ttp://hdl.handle.net/10362/141910
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RUN http://hdl.handle.net/10362/141910 Available 20220124

Neuroinflammation is a common feature of neurodegenerative diseases. Although it is still not consensual if itrepresents the cause or consequence of the development of suchpathologies, it is established that sustained pro-inflammatory glial responses can induce collateral damage in the host’s nervous system. In fact, glial hyperactivation of innate immune pathways, such as Nuclear Factor kappa-B (NF-κB), can impair neuronal activity and promote neuronal loss, leading tolong-term neurological impairments. Thus, the development of strategies to study and modulate glial NF-κB could enable the discovery of plausible therapeutic approaches to balance inflammation in the right direction, mitigating its deleterious effects. Akin to mammals, in Drosophilamelanogasterthe hyperactivation of NF-κB-like proteins, such as Relish, in glial cells has been demonstrated to cause neurodegeneration. Even though great progress has been made in thistopic,many aspects regarding inflammation-driven neuronal loss as well as the ability of Drosophilaglial cells to be immune responsive remain unclear andill-definedRecently, Low molecular weight (poly)phenols metabolites (LMWPM), which originated from fruit and vegetable human metabolism, such as Pyrogallol-sulfate, arose as promising candidates to control neuroinflammation, due to their described in vitroabilities to decreaseneuroinflammatory markersand their pleiotropic and positive effects in several mammalian and invertebrate neurodegenerative models. Therefore, we aimed to understand the immune responsive ability of fruit flies’glial cells andto develop a method in which we could study the anti-neuroinflammatory ability of LMWPM.In this study, we establisheda new paradigm to study in vivoNF-κB activation inDrosophila,in a neuroinflammatory context. We use a fused Relish-YFP proteintransgeneto track its activation upon exposure to gram-bacteria peptidoglycan, an inflammatory molecule known to activate Relish.Here, we identify,amongst the glial cells present in the peripheral nervous system, subperineurial and wrapping glia as immune responders and perineurial glia as non-responsive. Furthermore, we tested if our model was sensible to already known NF-κB inhibitors(such as Aspirin)andstudied the anti-neuroinflammatory potential of Pyrogallol-sulfate. We show thatAspirinpreventsPGN-dependent activation of Relish in glial cells. Moreover, we are the first to show that Pyrogallol-sulfatehas anti-neuroinflammatory propertiesin a multicellular organism, since we observe that it inhibits Relish PGN-dependent activation in glial cellsin 3rdinstar Drosophilalarvae. In summary, our findings provide a new in vivoneuroinflammatory model to dissect the molecular and cellular mechanisms behind neuroinflammation in Drosophila, filling the gaps regarding the way the fruit flies’ nervous system responds to inflammatory molecules. Additionally, our new method demonstrates the potential of Drosophilafor the versatile and fast screening of potential anti-neuroinflammatory compounds, paving the way for the discovery of plausible new therapeutics for controlling neuroinflammation and mitigating the impactof neurodegenerative diseases.

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