Search

Aims: Although programmed cell death protein 1 (PD‐1) typically serves as a target for immunotherapies, a few recent studies have found that PD‐1 is expressed in the nervous system and that neuronal PD‐1 might play a crucial role in regulating neuronal excitability. However, whether brain‐localized PD‐1 is involved in seizures and epileptogenesis is still unknown and worthy of in‐depth exploration. Methods: The existence of PD‐1 in human neurons was confirmed by immunohistochemistry, and PD‐1 expression levels were measured by real‐time quantitative PCR (RT‐qPCR) and western blotting. Chemoconvulsants, pentylenetetrazol (PTZ) and cyclothiazide (CTZ), were applied for the establishment of in vivo (rodents) and in vitro (primary hippocampal neurons) models of seizure, respectively. SHR‐1210 (a PD‐1 monoclonal antibody) and sodium stibogluconate (SSG, a validated inhibitor of SH2‐containing protein tyrosine phosphatase‐1 [SHP‐1]) were administrated to investigate the impact of PD‐1 pathway blockade on epileptic behaviors of rodents and epileptiform discharges of neurons. A miRNA strategy was applied to determine the impact of PD‐1 knockdown on neuronal excitability. The electrical activities and sodium channel function of neurons were determined by whole‐cell patch‐clamp recordings. The interaction between PD‐1 and α‐6 subunit of human voltage‐gated sodium channel (Nav1.6) was validated by performing co‐immunostaining and co‐immunoprecipitation (co‐IP) experiments. Results: Our results reveal that PD‐1 protein and mRNA levels were upregulated in lesion cores compared with perifocal tissues of surgically resected specimens from patients with intractable epilepsy. Furthermore, we show that anti‐PD‐1 treatment has anti‐seizure effects both in vivo and in vitro. Then, we reveal that PD‐1 blockade can alter the electrophysiological properties of sodium channels. Moreover, we reveal that PD‐1 acts together with downstream SHP‐1 to regulate sodium channel function and hence neuronal excitability. Further investigation suggests that there is a direct interaction between neuronal PD‐1 and Nav1.6. Conclusion: Our study reveals that neuronal PD‐1 plays an important role in epilepsy and that anti‐PD‐1 treatment protects against seizures by suppressing sodium channel function, identifying anti‐PD‐1 treatment as a novel therapeutic strategy for epilepsy. [ABSTRACT FROM AUTHOR]

TGF-β plays an important role in the induction of Treg and maintenance of immunologic tolerance, but whether other members of TGF-β superfamily act together or independently to achieve this effect is poorly understood. Although others have reported that the bone morphogenetic proteins (BMP) and TGF-β have similar effects on the development of thymocytes and T cells, in this study, we report that members of the BMP family, BMP-2 and -4, are unable to induce non-regulatory T cells to become Foxp3 [ABSTRACT FROM AUTHOR]

TGF-beta plays an important role in the induction of Treg and maintenance of immunologic tolerance, but whether other members of TGF-beta superfamily act together or independently to achieve this effect is poorly understood. Although others have reported that the bone morphogenetic proteins (BMP) and TGF-beta have similar effects on the development of thymocytes and T cells, in this study, we report that members of the BMP family, BMP-2 and -4, are unable to induce non-regulatory T cells to become Foxp3+ Treg. Neutralization studies with Noggin have revealed that BMP-2/4 and the BMP receptor signaling pathway is not required for TGF-beta to induce naïve CD4+CD25- cells to express Foxp3; however, BMP-2/4 and TGF-beta have a synergistic effect on the induction of Foxp3+ Treg. BMP-2/4 affects non-Smad signaling molecules including phosphorylated ERK and JNK, which could subsequently promote the differentiation of Foxp3+ Treg induced by TGF-beta. Data further advocate that TGF-beta is a key signaling factor for Foxp3+ Treg development. In addition, the synergistic effect of BMP-2/4 and TGF-beta indicates that the simultaneous manipulation of TGF-beta and BMP signaling might have considerable effects in the clinical setting for the enhancement of Treg purity and yield.