Abstract
Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.
Highlights
Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders
To shed some light on the mechanisms underlying the regulation of LPS effects by PTN, we studied the phosphorylation of signal transducer and activator of transcription-3 (STAT3), as a key event of the LPS/Toll Like Receptor 4 (TLR4) signaling pathway, and proinflammatory markers in the same experimental paradigm: LPS (7.5 mg/kg)-injected Ptn-Tg mice
We found that LPS induced a robust phosphorylation of STAT3 in the prefrontal cortex (PFC) of wild type (Wt) and Ptn-Tg mice 16 h after LPS administration (Fig. 1a,b, P = 0.0002); we did not observe differences between genotypes (Fig. 1a,b)
Summary
Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. PTN binds RPTPβ/ζ11, which is mainly expressed in the adult CNS in different cells including neurons and microglia[8,12], and inactivates its phosphatase activity. This mechanism modulates the tyrosine phosphorylation of substrates of RPTPβ/ζ that are involved in neuroinflammation such as Anaplastic Lymphoma Kinase (ALK)[13] and Fyn kinase[14]. ALK is a known regulator of the activation of STAT317, suggesting a possible cross-talk between the PTN/RPTPβ/ζ and LPS signaling pathways Despite this evidence, the possible modulatory role of RPTPβ/ζ on glial responses and neuroinflammation has not been studied yet
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