Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

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.

Single‐cell RNA‐sequencing analysis reveals enhanced non‐canonical neurotrophic factor signaling in the subacute phase of traumatic brain injury

“…MDK deficiency reduces M1 phenotype microglia/macrophage infiltration after TBI 55 . Overexpression of PTN in mice significantly enhances LPS‐induced inflammatory cytokine expression 56,57 . Transplantation of PSAP‐deficient bone marrow into low‐density lipoprotein receptor knockout mice decreases plaque inflammation in atherosclerosis 37 .…”

“… 55 Overexpression of PTN in mice significantly enhances LPS‐induced inflammatory cytokine expression. 56 , 57 Transplantation of PSAP‐deficient bone marrow into low‐density lipoprotein receptor knockout mice decreases plaque inflammation in atherosclerosis. 37 These studies suggest that MDK, PTN, and PSAP play a pro‐inflammatory role.…”

Inhibition of RPTPβ/ζ reduces chronic ethanol intake in adolescent mice and modulates ethanol effects on hippocampal neurogenesis and glial responses in a sex-dependent manner

“…The RPTPβ/ζ signalling pathway is involved in the regulation of the neuroimmune response to different stimuli ( Herradon et al, 2019 ). Accordingly, we have shown that inhibition of RPTPβ/ζ with MY10 potentiates LPS-induced microglial responses ( Fernández-Calle et al, 2020 ). Thus, in the present study we aimed to test the possibility that RPTPβ/ζ inhibition modulates IAE-induced changes in glial responses in the dentate gyrus.…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…However, also in view of the recent compelling data that come from multiple behavioral studies in mice ( Cressant et al, 2017 ; Fernandez-Calle et al, 2018 ; Fujikawa et al, 2019 ; Tanga et al, 2019 ) it is a matter of time to be able to pinpoint PTPRZ1 variants as components in the multifactorial central nervous system disorders. Studies involving Ptprz1 mutant mice and various cell models have established a regulatory role in neuroinflammation and (re)myelination ( Fujikawa and Noda, 2016 ; Fernandez-Calle et al, 2020 ; Nagai et al, 2022 ), and thus multiple sclerosis as disease link also comes to mind. This is, however, as yet not supported by human PTPRZ1 mutations associating with this chronic inflammatory demyelinating disorder.…”