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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- chemotaxis --- chemokine --- atypical chemokine receptor --- G protein-coupled receptor --- signaling --- arrestin --- GPCR --- chemotaxis --- chemokine --- atypical chemokine receptor --- G protein-coupled receptor --- signaling --- arrestin --- GPCR

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

chemotaxis --- chemokine --- atypical chemokine receptor --- G protein-coupled receptor --- signaling --- arrestin --- GPCR

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Alzheimer disease is the most frequent neurodegenerative disease, which is characterized by the extracellular accumulation in the brain of the amyloid peptide Aβ. Aβ peptide is produced by two distinct cleavages of its precursor APP. Currently, the function of APP is not known, although the cellular metabolism of the protein was characterized in detail. APP undergoes an intramembrane cleavage by a γ-secretase activity also able to cleave the Notch protein. This cleavage releases the intracellular domain of Notch (Notch Intra Cellular Domain NICD) which is a transcription factor. The cleavage of APP by γ-secretase releases the AICD fragment which, by analogy with the NICD, could control gene transcription. The identification of several genes whose transcription would be controlled by APP could not be confirmed. Therefore, the role of APP in regulation of gene transcription remains questionable.
The aim of this work was to identify genes whose transcription would be controlled by APP and to study the mechanisms involved in this regulation.
The comparative analysis of the transcriptomes from embryonic fibroblasts (MEFs) cultured from wild-type mouse (APP+/+) or APP knocked-out mouse (APP-/-) made it possible to identify several genes whose expression was modified in an important way by the expression of APP. Among these genes, we focused on that coding CXCL5, a pro-inflammatory chemokine which could be involved in neuro inflammation, and whose receptor, CXCR2, is present on neurons. The expression of CXCL5 mRNA (quantitative RT-PCR) and protein (ELISA) was controlled by the presence of the APP in MEFs. The promoter of the CXCL5 gene was cloned upstream the luciferase reporter gene. The weak transcriptional activity of this promoter was similar in APP +/+ and APP-/- MEFs. The stability of the CXCL5 mRNA, measured in the presence of actinomycine D, was also identical in the two cell types. In APP +/+ MEFs, transcription of the CXCL5 gene was inhibited by trichostatin A, a specific inhibitor of the type I and type II histone deacetylases (HDACs). The transcription of the CXCL5 gene was also very sensitive to methylation. These results suggest an implication of APP in the epigenetic control of the expression of CXCL5. This APP-mediated control of CXCL5 expression was also observed in primary cultures of astrocytes, as well as in vivo, in transgenic mice La maladie d’Alzheimer est la maladie neurodégénérative la plus fréquente. Elle est caractérisée, entre autre, par l’accumulation extracellulaire du peptide amyloïde Aβ dans le cerveau. Le peptide Aβ est produit par deux clivages distincts de son précurseur, le précurseur du peptide amyloïde (APP).
Actuellement, la fonction de l’APP n’est pas connue, bien que le métabolisme cellulaire de la protéine ait été caractérisé en détail. L’APP subit un clivage intramembranaire par une activité γ-sécrétase capable également de cliver la protéine Notch. Ce clivage libère le domaine intracellulaire de Notch (Notch Intra Cellular Domain NICD) qui est un facteur de transcription. Le clivage de l’APP par la γ-sécrétase libère le fragment AICD qui, par analogie avec le NICD, pourrait réguler la transcription. L’identification de certains gènes dont la transcription serait régulée par l’APP n’a pu être confirmée, et cette hypothèse reste donc très controversée.
Le but de ce mémoire était d’identifier des gènes dont la transcription serait régulée par l’APP et d’étudier les mécanismes impliqués dans cette régulation.
L’analyse comparative des transcriptomes de fibroblastes embryonnaires (MEFs) provenant de souris wild-type (APP+/+) et APP knock-out (APP-/-) a permis d’identifier certains gènes dont l’expression est modifiée de manière importante par l’expression d’APP. Parmi ces gènes, celui codant CXCL5 a retenu notre attention. CXCL5 est une chémokine pro-inflammatoire qui pourrait intervenir dans des phénomènes de neuro-inflammation et dont le récepteur, CXCR2, est présent sur les neurones. L’expression du mRNA (RT-PCR quantitative) et de la protéine (ELISA) CXCL5 est contrôlée par la présence de l’APP dans les MEFs. Le promoteur du gène CXCL5 a été cloné en amont d’un gène rapporteur luciférase. L’activité transcriptionnelle faible de ce promoteur est semblable dans des cellules MEFs APP +/+ et APP-/-. La stabilité du mRNA de CXCL5, mesurée en présence d’actinomycine D, est également identique dans les deux types cellulaires. Dans des cellules APP +/+, la transcription du gène de CXCL5 est influencée par la trichostatine A, un inhibiteur spécifique des histones déacétylases (HDACs) de type I et de type II. La transcription du gène CXCL5 est également très sensible à la méthylation. Ces résultats suggèrent une implication de l’APP dans le contrôle épigénétique de l’expression de CXCL5. Ce contrôle de l’expression de CXCL5 par l’APP a pu également être observé dans des astrocytes en culture primaire et in vivo, dans des souris transgéniques

Alzheimer Disease --- Alzheimer Disease --- Amyloid beta-Protein Precursor --- Chemokine CXCL5

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- chemokine --- CVB3 --- Hantavirus --- hcmv --- HIV --- Inflammation --- influenza --- interferon

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In the Research Topic "History of Chemoattractant Research" we will portray some of the key discoveries that helped to transform cell migration research into a global playing field within immunology (and beyond). Early progress had a profound effect on both, academia and industry. Today, numerous academic laboratories are fully engaged in compiling a detailed road map describing the highly complex network of immune and tissue cells that respond to chemoattractants. Industrial research, on the other hand, centers on drugs that interfere with immune cell traffic in inflammatory diseases and cancer. The following series of “short stories” provide personal accounts on key discoveries. The individual molecular discoveries enabled numerous research laboratories worldwide to unravel their significance in steady-state or pathological immune processes. Although ground-breaking in their own right, it is therefore worth emphasizing that rapid progress in chemoattractant research was made possible by many other laboratories who were not directly involved in the original discovery process. Therefore, the authors of this mini-series are discussing their findings in the context of time, place and subsequent progress enabled by their discoveries. It is hoped that a wide readership will find these accounts entertaining as well as educational although those who wish to gain a more detailed knowledge are referred to the many outstanding reviews on chemokines and other chemoattractants.

Homing --- chemokine --- tumour --- cell migration --- Inflammation --- Chemotaxis --- Immunity --- immune surveillance