The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair

Davide Lecca, Maria Letizia Trincavelli, Paolo Gelosa, Luigi Sironi, Paolo Ciana, Marta Fumagalli, Giovanni Villa, Claudia Verderio, Carlotta Grumelli, Uliano Guerrini, Elena Tremoli, Patrizia Rosa, Serena Cuboni, Claudia Martini, Annalisa Buffo, Mauro Cimino, Maria P. Abbracchio

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs), two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as "danger signals" to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDP-glucose and LTD4), is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immuno-labeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17+ oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDP-glucose and LTD4 promoted the expression of myelin basic protein, confirming progression toward mature oligodendrocytes. Thus, GPR17 may act as a "sensor" that is activated upon brain injury on several embryonically distinct cell types, and may play a key role in both inducing neuronal death inside the ischemic core and in orchestrating the local remodeling/ repair response. Specifically, we suggest GPR17 as a novel target for therapeutic manipulation to foster repair of demyelinating wounds, the types of lesions that also occur in patients with multiple sclerosis.

Original languageEnglish
Article numbere3579
JournalPLoS One
Volume3
Issue number10
DOIs
Publication statusPublished - Oct 31 2008

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brain damage
Oligodendroglia
Brain
Repair
brain
receptors
Sensors
Brain Injuries
Uridine Diphosphate Glucose
Leukotriene D4
Neurons
Microglia
leukotrienes
neurons
neuroglia
ischemia
Ischemia
Uracil Nucleotides
nucleotides
Telencephalon

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. / Lecca, Davide; Trincavelli, Maria Letizia; Gelosa, Paolo; Sironi, Luigi; Ciana, Paolo; Fumagalli, Marta; Villa, Giovanni; Verderio, Claudia; Grumelli, Carlotta; Guerrini, Uliano; Tremoli, Elena; Rosa, Patrizia; Cuboni, Serena; Martini, Claudia; Buffo, Annalisa; Cimino, Mauro; Abbracchio, Maria P.

In: PLoS One, Vol. 3, No. 10, e3579, 31.10.2008.

Research output: Contribution to journalArticle

Lecca, D, Trincavelli, ML, Gelosa, P, Sironi, L, Ciana, P, Fumagalli, M, Villa, G, Verderio, C, Grumelli, C, Guerrini, U, Tremoli, E, Rosa, P, Cuboni, S, Martini, C, Buffo, A, Cimino, M & Abbracchio, MP 2008, 'The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair', PLoS One, vol. 3, no. 10, e3579. https://doi.org/10.1371/journal.pone.0003579
Lecca, Davide ; Trincavelli, Maria Letizia ; Gelosa, Paolo ; Sironi, Luigi ; Ciana, Paolo ; Fumagalli, Marta ; Villa, Giovanni ; Verderio, Claudia ; Grumelli, Carlotta ; Guerrini, Uliano ; Tremoli, Elena ; Rosa, Patrizia ; Cuboni, Serena ; Martini, Claudia ; Buffo, Annalisa ; Cimino, Mauro ; Abbracchio, Maria P. / The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. In: PLoS One. 2008 ; Vol. 3, No. 10.
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AU - Ciana, Paolo

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AU - Villa, Giovanni

AU - Verderio, Claudia

AU - Grumelli, Carlotta

AU - Guerrini, Uliano

AU - Tremoli, Elena

AU - Rosa, Patrizia

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AU - Abbracchio, Maria P.

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N2 - Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs), two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as "danger signals" to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDP-glucose and LTD4), is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immuno-labeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17+ oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDP-glucose and LTD4 promoted the expression of myelin basic protein, confirming progression toward mature oligodendrocytes. Thus, GPR17 may act as a "sensor" that is activated upon brain injury on several embryonically distinct cell types, and may play a key role in both inducing neuronal death inside the ischemic core and in orchestrating the local remodeling/ repair response. Specifically, we suggest GPR17 as a novel target for therapeutic manipulation to foster repair of demyelinating wounds, the types of lesions that also occur in patients with multiple sclerosis.

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