iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Adv...

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Autores principales:	Katja Badanjak, Patrycja Mulica, Semra Smajic, Sylvie Delcambre, Leon-Charles Tranchevent, Nico Diederich, Thomas Rauen, Jens C. Schwamborn, Enrico Glaab, Sally A. Cowley, Paul M. A. Antony, Sandro L. Pereira, Carmen Venegas, Anne Grünewald
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	microglia iPSC neuroinflammation idiopathic Parkinson’s disease disease modeling Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e67011a883074525b6799daeb3e433fd
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spelling	oai:doaj.org-article:e67011a883074525b6799daeb3e433fd2021-11-05T09:27:56ZiPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease2296-634X10.3389/fcell.2021.740758https://doaj.org/article/e67011a883074525b6799daeb3e433fd2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.740758/fullhttps://doaj.org/toc/2296-634XParkinson’s disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions—a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.Katja BadanjakPatrycja MulicaSemra SmajicSylvie DelcambreLeon-Charles TrancheventNico DiederichThomas RauenJens C. SchwambornEnrico GlaabSally A. CowleyPaul M. A. AntonyPaul M. A. AntonySandro L. PereiraCarmen VenegasAnne GrünewaldAnne GrünewaldFrontiers Media S.A.articlemicrogliaiPSCneuroinflammationidiopathic Parkinson’s diseasedisease modelingBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microglia iPSC neuroinflammation idiopathic Parkinson’s disease disease modeling Biology (General) QH301-705.5
spellingShingle	microglia iPSC neuroinflammation idiopathic Parkinson’s disease disease modeling Biology (General) QH301-705.5 Katja Badanjak Patrycja Mulica Semra Smajic Sylvie Delcambre Leon-Charles Tranchevent Nico Diederich Thomas Rauen Jens C. Schwamborn Enrico Glaab Sally A. Cowley Paul M. A. Antony Paul M. A. Antony Sandro L. Pereira Carmen Venegas Anne Grünewald Anne Grünewald iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
description	Parkinson’s disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions—a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.
format	article
author	Katja Badanjak Patrycja Mulica Semra Smajic Sylvie Delcambre Leon-Charles Tranchevent Nico Diederich Thomas Rauen Jens C. Schwamborn Enrico Glaab Sally A. Cowley Paul M. A. Antony Paul M. A. Antony Sandro L. Pereira Carmen Venegas Anne Grünewald Anne Grünewald
author_facet	Katja Badanjak Patrycja Mulica Semra Smajic Sylvie Delcambre Leon-Charles Tranchevent Nico Diederich Thomas Rauen Jens C. Schwamborn Enrico Glaab Sally A. Cowley Paul M. A. Antony Paul M. A. Antony Sandro L. Pereira Carmen Venegas Anne Grünewald Anne Grünewald
author_sort	Katja Badanjak
title	iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
title_short	iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
title_full	iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
title_fullStr	iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
title_full_unstemmed	iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease
title_sort	ipsc-derived microglia as a model to study inflammation in idiopathic parkinson’s disease
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e67011a883074525b6799daeb3e433fd
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iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

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