Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state

Alessandro Villa, Barbara Klein, Bieneke Janssen, Jordi Pedragosa, Giovanna Pepe, Bastian Zinnhardt, Danielle J. Vugts, Paolo Gelosa, Luigi Sironi, Wissam Beaino, Annelaure Damont, Frédéric Dollé, Benoit Jego, Alexandra Winkeler, Dieter Ory, Olof Solin, Johnny Vercouillie, Uta Funke, Sandra Laner-Plamberger, Linda V. Blomster & 7 others Palle Christophersen, Elisabetta Vegeto, Ludwig Aigner, Andreas Jacobs, Anna M. Planas, Adriana Maggi, Albert D. Windhorst

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.
Original languageEnglish
Pages (from-to)5400-5418
Number of pages19
JournalTheranostics
Volume8
Issue number19
DOIs
Publication statusPublished - 2018

Cite this

Villa, Alessandro ; Klein, Barbara ; Janssen, Bieneke ; Pedragosa, Jordi ; Pepe, Giovanna ; Zinnhardt, Bastian ; Vugts, Danielle J. ; Gelosa, Paolo ; Sironi, Luigi ; Beaino, Wissam ; Damont, Annelaure ; Dollé, Frédéric ; Jego, Benoit ; Winkeler, Alexandra ; Ory, Dieter ; Solin, Olof ; Vercouillie, Johnny ; Funke, Uta ; Laner-Plamberger, Sandra ; Blomster, Linda V. ; Christophersen, Palle ; Vegeto, Elisabetta ; Aigner, Ludwig ; Jacobs, Andreas ; Planas, Anna M. ; Maggi, Adriana ; Windhorst, Albert D. / Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state. In: Theranostics. 2018 ; Vol. 8, No. 19. pp. 5400-5418.
@article{e3a7b8abd91b4441b3f8b5005ea494de,
title = "Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state",
abstract = "Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.",
author = "Alessandro Villa and Barbara Klein and Bieneke Janssen and Jordi Pedragosa and Giovanna Pepe and Bastian Zinnhardt and Vugts, {Danielle J.} and Paolo Gelosa and Luigi Sironi and Wissam Beaino and Annelaure Damont and Fr{\'e}d{\'e}ric Doll{\'e} and Benoit Jego and Alexandra Winkeler and Dieter Ory and Olof Solin and Johnny Vercouillie and Uta Funke and Sandra Laner-Plamberger and Blomster, {Linda V.} and Palle Christophersen and Elisabetta Vegeto and Ludwig Aigner and Andreas Jacobs and Planas, {Anna M.} and Adriana Maggi and Windhorst, {Albert D.}",
year = "2018",
doi = "10.7150/thno.25572",
language = "English",
volume = "8",
pages = "5400--5418",
journal = "Theranostics",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
number = "19",

}

Villa, A, Klein, B, Janssen, B, Pedragosa, J, Pepe, G, Zinnhardt, B, Vugts, DJ, Gelosa, P, Sironi, L, Beaino, W, Damont, A, Dollé, F, Jego, B, Winkeler, A, Ory, D, Solin, O, Vercouillie, J, Funke, U, Laner-Plamberger, S, Blomster, LV, Christophersen, P, Vegeto, E, Aigner, L, Jacobs, A, Planas, AM, Maggi, A & Windhorst, AD 2018, 'Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state' Theranostics, vol. 8, no. 19, pp. 5400-5418. https://doi.org/10.7150/thno.25572

Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state. / Villa, Alessandro; Klein, Barbara; Janssen, Bieneke; Pedragosa, Jordi; Pepe, Giovanna; Zinnhardt, Bastian; Vugts, Danielle J.; Gelosa, Paolo; Sironi, Luigi; Beaino, Wissam; Damont, Annelaure; Dollé, Frédéric; Jego, Benoit; Winkeler, Alexandra; Ory, Dieter; Solin, Olof; Vercouillie, Johnny; Funke, Uta; Laner-Plamberger, Sandra; Blomster, Linda V.; Christophersen, Palle; Vegeto, Elisabetta; Aigner, Ludwig; Jacobs, Andreas; Planas, Anna M.; Maggi, Adriana; Windhorst, Albert D.

In: Theranostics, Vol. 8, No. 19, 2018, p. 5400-5418.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state

AU - Villa, Alessandro

AU - Klein, Barbara

AU - Janssen, Bieneke

AU - Pedragosa, Jordi

AU - Pepe, Giovanna

AU - Zinnhardt, Bastian

AU - Vugts, Danielle J.

AU - Gelosa, Paolo

AU - Sironi, Luigi

AU - Beaino, Wissam

AU - Damont, Annelaure

AU - Dollé, Frédéric

AU - Jego, Benoit

AU - Winkeler, Alexandra

AU - Ory, Dieter

AU - Solin, Olof

AU - Vercouillie, Johnny

AU - Funke, Uta

AU - Laner-Plamberger, Sandra

AU - Blomster, Linda V.

AU - Christophersen, Palle

AU - Vegeto, Elisabetta

AU - Aigner, Ludwig

AU - Jacobs, Andreas

AU - Planas, Anna M.

AU - Maggi, Adriana

AU - Windhorst, Albert D.

PY - 2018

Y1 - 2018

N2 - Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

AB - Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85043451631&origin=inward

U2 - 10.7150/thno.25572

DO - 10.7150/thno.25572

M3 - Article

VL - 8

SP - 5400

EP - 5418

JO - Theranostics

JF - Theranostics

SN - 1838-7640

IS - 19

ER -