New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

Schwann cells (SCs) are peripheral myelinating glial cells that express the neuronal Ca 2+ -dependent cell adhesion molecule, neural cadherin (N-cadherin). Ncadherin is involved in glia-glia and axon-glia interactions and participates in many key events, which range from the control of axonal growth and guidance to synapse formation and plasticity. Extracellular UTP activates P2Y purinergic receptors and exerts short-and long-term effects on several tissues to promote wound healing. Nevertheless, the contribution of P2Y receptors in peripheral nervous system functions is not completely understood. The current study demonstrated that UTP induced a dose-and timedependent increase in N-cadherin expression in SCs. Furthermore, N-cadherin expression was blocked by the P2 purinoceptor antagonist suramin. The increased N-cadherin expression induced by UTP was mediated by phosphorylation of mitogen-activated protein kinases (MAPKs), such as Jun N-terminal kinase, extracellular-regulated kinase and p38 kinase. Moreover, the Rho kinase inhibitor Y27632, the phospholipase C inhibitor U73122 and the protein kinase C inhibitor calphostin C attenuated the UTP-induced activation of MAPKs significantly. Extracellular UTP also modulated increased in the expression of the early transcription factors c-Fos and c-Jun. We also demonstrated that the region of the N-cadherin promoter between nucleotide positions −3698 and −2620, which contained one activator protein-1-binding site, was necessary for UTP-induced gene expression. These results suggest a novel role for P2Y purinergic receptors in the regulation of N-cadherin expression in SCs.

Section: Discussionmentioning

confidence: 99%

N-cadherin expression is regulated by UTP in schwannoma cells

Martiáñez

Lamarca

Casals

et al. 2012

“…While several reports have shown that nucleotides can induce the migration of different cell types in culture [27], cell migration is a complex coordinated process of cell polarization, protrusion of the cytoplasm, adhesion, and forward displacement of the cell [38]. In the present study, live imaging experiments revealed that in cultures that were treated with apyrase, glial cells at the border of the scratch formed only small cytoplasmic protrusions that soon retracted toward the cell soma.…”

Section: Discussionmentioning

confidence: 38%

“…Since nucleotides induce the expression of N-cadherin in cultured astrocytes [42] as well as in transformed cells [43], one Cell migration entails activation of a variety of molecular and cellular events that converge in morphological changes and cell displacement. Different intracellular signaling pathways activated by membrane receptors were implicated in these events, including nucleotide receptors [27]. For example, phosphorylation of Akt and FAK induced by nucleotides and EGF were associated with migration of neural stem cells [30].…”

Section: Discussionmentioning

confidence: 99%

“…Besides proliferation, nucleotides also regulate migration and/or chemotaxis of a broad range of cell types, including immune cells, cardiac fibroblasts, epithelial, endothelial, or tumor cells, keratinocytes, and microglia [27]. During CNS development, nucleotides induce the migration of astrocyte progenitors [28] and neural stem cells [29].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of nucleotides in glial growth following scratch injury in avian retinal cell monolayer cultures

Silva

França

Ornelas

et al. 2015

When retinal cell cultures were mechanically scratched, cell growth over the empty area was observed. Only dividing and migrating, 2 M6-positive glial cells were detected. Incubation of cultures with apyrase (APY), suramin, or Reactive Blue 2 (RB-2), but not MRS 2179, significantly attenuated the growth of glial cells, suggesting that nucleotide receptors other than P2Y 1 are involved in the growth of glial cells. UTPγS but not ADPβS antagonized apyrase-induced growth inhibition in scratched cultures, suggesting the participation of UTP-sensitive receptors. No decrease in proliferating cell nuclear antigen (PCNA + ) cells was observed at the border of the scratch in apyrase-treated cultures, suggesting that glial proliferation was not affected. In apyrase-treated cultures, glial cytoplasm protrusions were smaller and unstable. Actin filaments were less organized and alfa-tubulinlabeled microtubules were mainly parallel to scratch. In contrast to control cultures, very few vinculin-labeled adhesion sites could be noticed in these cultures. Increased Akt and ERK phosphorylation was observed in UTP-treated cultures, effect that was inhibited by SRC inhibitor 1 and PI3K blocker LY294002. These inhibitors and the FAK inhibitor PF573228 also decreased glial growth over the scratch, suggesting participation of SRC, PI3K, and FAK in UTP-induced growth of glial cells in scratched cultures. RB-2 decreased dissociated glial cell attachment to fibronectin-coated dishes and migration through transwell membranes, suggesting that nucleotides regulated adhesion and migration of glial cells. In conclusion, mechanical scratch of retinal cell cultures induces growth of glial cells over the empty area through a mechanism that is dependent on activation of UTP-sensitive receptors, SRC, PI3K, and FAK.

“…Released by damaged or stressed cells, extracellular ATP acts as a danger signal and induces inflammasome activation, as well as the release of inflammatory cytokines, being strong pro-inflammatory stimuli. Extracellular ATP also promotes phagocyte chemotaxis and leads to damaged cell clearance, as beautifully revised by Corriden and Insel [8]. Accumulated extracellular ATP gradually suffers enzymatic hydrolysis into adenosine, which, in turn, is read as a Breporter of excessive tissue damage,^as shown by Bono et al [9] As such, adenosine signaling is interpreted as an anti-inflammatory stimulus, generally opposing the effects induced by ATP.…”

Section: Extracellular Adenosine Production and Adenosine Signalingmentioning

confidence: 97%

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. This nucleotide is produced, in part, by the action of the ectoenzymes CD39 and CD73. Interestingly, these proteins are expressed on the cell surface of regulatory T-cells (Tregs) and mesenchymal stromal cells (MSCs)-two cell populations that have emerged as potential therapeutic tools in the field of cell therapy. In fact, the production of adenosine constitutes a mechanism used by both cell types to control the immune response. Recently, great scientific progress was obtained regarding the role of adenosine in the inflammatory environment. In this context, the present review focuses on the advances related to the impact of adenosine production over the immune modulatory activity of Tregs and MSCs, and how this nucleotide controls the biological functions of these cells. Finally, we mention the main challenges and hurdles to bring such molecule to clinical settings.