The Recently Identified P2Y-Like Receptor GPR17 Is a Sensor of Brain Damage and a New Target for Brain Repair

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.

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

“…No co‐localization was found with either microglial, astrocytic or neuronal markers, like IBA1, GFAP, and MAP2, respectively (Figure 1e–g). Thus, we confirmed that also in spinal cord, as previously shown for brain (Lecca et al, 2008; Boda et al, 2011; Ceruti et al, 2011), GPR17 is specifically expressed in a subset of oligodendrocyte precursors at intermediate stages of differentiation.…”

“…To detail the final fate of the GPR17‐expressing cells and to unveil whether they indeed become functionally mature myelinating oligodendrocytes, we took advantage of the first inducible fluorescent GPR17 reporter mouse line for fate mapping studies (GPR17‐iCreER T2 xCAG‐eGFP mice), where, upon tamoxifen treatment, all GPR17‐expressing cells at that specific moment become permanently fluorescent, and can be traced throughout life (Viganò et al, 2016). Since, as already mentioned, GPR17 is only transiently expressed by OPCs and is no longer present in mature myelinating oligodendrocytes (Lecca et al, 2008; Fumagalli et al, 2011; Fumagalli et al, 2015) this transgenic mouse line represents the only possible means to follow in vivo the final destiny of the GPR17 + pool of OPCs, even after cells have physiologically downregulated the receptor along their differentiation pathway.…”

“…Any alterations in this precise expression pattern result in myelination defects (Chen et al, 2009; Fumagalli et al, 2011; Fumagalli et al, 2015). Pathologically increased levels of GPR17 have been found after focal lysolecithin induced demyelination (Boda et al, 2011), following brain ischemia in rodents subjected to middle cerebral artery occlusion (MCAO) (Ciana et al, 2006; Lecca et al, 2008) and after traumatic brain injury in both rodents (Boda et al, 2011) and human subjects (Franke et al, 2013). In initial studies, the mRNA for GPR17 was also found to be increased in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) and in the spinal lesions of multiple sclerosis patients (Chen et al, 2009).…”

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

“…Gpr17-knockout mice show early-onset oligodendrocyte myelination, while Gpr17 overexpression inhibits oligodendrocyte differentiation and maturation both in vivo and in vitro [26] . However, another study showed that treatment with the endogenous GPR17 ligand UDP-glucose promotes the differentiation of oPCs into mature myelin basic protein-positive oligodendrocytes [30] .…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…There are an increasing number of pathways and mechanisms being identified that could potentially play similar roles [85][86][87][88]. As previously indicated, such research could impact not only MS, but other myelin disorders, such as periventricular leukomalacia (PVL), in which a critical window for repair is inadequately addressed by current therapies.…”