There has been no significant improvements for immune checkpoint inhibitors since its first use. Tumour-associated macrophages (TAMs) are critical mediators in the PD-1/PD-L1 axis, contributing to the immunosuppressive tumour microenvironment. This study aims to investigate the potential role of PD-L1 in regulating TAMs in glioblastoma. Gene expression data and clinical information of glioma patients were collected from TCGA (n = 614) and CGGA (n = 325) databases. Differentially expressed genes between PD-L1^high and PD-L1^low groups were identified and subjected to bioinformatical analysis. We found that PD-L1 was frequently expressed in gliomas with a grade-dependent pattern. Higher PD-L1 expression predicted shorter overall survival. Moreover, PD-L1 was positively correlated with immunosuppressive cells (macrophage, neutrophil and immature DC) and negatively correlated with cytocidal immune cells (CD8⁺ T cell and Th1). Importantly, PD-L1 high expression was significantly correlated with M2-polarization of macrophages (M2-TAMs). We conclude that PD-L1 is an unfavourable prognostic marker for patients with glioblastoma; PD-L1-mediated immunosuppression may attribute to the infiltration and M2-polarization of TAMs.

Parkinson’s disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. However, whether abnormal miR-124 expression could regulate the activation of microglia remains poorly understood. BV2 cells were activated by exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed. Over-expression and knockdown studies of miR-124 were performed to observe the effects on MEKK3/NF-κB signalling pathways, and the induction of pro-inflammatory and neurotoxic factors was assessed. In addition, a luciferase reporter assay was conducted to confirm whether MEKK3 is a direct target of miR-124. Meanwhile, production of miR-124, MEKK3, and p-p65; midbrain DA neuronal death; or activation of microglia were analysed when treated with or without miR-124 in the MPTP-induced model of PD. We found that the knockdown of MEKK3 could inhibit the activation of microglia by regulating NF-κB expression. Over-expression of miR-124 could effectively attenuate the LPS-induced expression of pro-inflammatory cytokines and promote the secretion of neuroprotective factors. We also first identified a unique role of miR-124 in mediating the microglial inflammatory response by targeting MEKK3/NF-κB signalling pathways. In the microglial culture supernatant (MCS) transfer model, over-expression of the miR-124 or knockdown of MEKK3 in BV2 cells prevented SH-SY5Y from apoptosis and death. Moreover, MEKK3 and p-p65 were abundantly expressed in the midbrain. Furthermore, their expression levels increased and microglial activation was observed in the MPTP-induced model of PD. In addition, exogenous delivery of miR-124 could suppress MEKK3 and p-p65 expression and attenuate the activation of microglia in the substantia nigra pars compacta of MPTP-treated mice. miR-124 also could prevent MPTP-dependent apoptotic midbrain DA cell death in a MPTP-induced PD model. Taken together, our data suggest that miR-124 can inhibit neuroinflammation in the development of PD by regulating the MEKK3/NF-κB signalling pathways and implicate miR-124 as a potential therapeutic target for regulating the inflammatory response in PD.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). www.fasebj.org

Intracranial haemorrhage (ICH) is a life-threatening type of stroke with high mortality, morbidity, and recurrence rates. However, no effective treatment has been established to improve functional outcomes in patients with ICH to date. Strategies targeting secondary brain injury are of great interest in both experimental and translational studies. The immune system is increasingly considered to be a crucial contributor to ICH-induced brain injury because it participates in multiple phases of ICH, from the early vascular rupture events to brain recovery. Various pathobiological processes that contribute to secondary brain injury closely interact with the immune system, such as brain oedema, neuroinflammation, and neuronal damage. Hence, we summarize the immune response to ICH and recent progress in treatments targeting the immune system in this review. The emerging therapeutic strategies that target the immune system after ICH are a particular focus and have been summarized.

The role of microglial-mediated sustained neuroinflammation in the onset and progression of Parkinson’s disease (PD) is well established, but the mechanisms contributing to microglial activation remain unclear. LincRNA-p21, a well studied long intergenic noncoding RNA (lincRNA), plays pivotal roles in diverse biological processes and diseases. Its role in microglial activation and inflammation-induced neurotoxicity, however, has not yet been fully elucidated. Here, we report that lincRNA-p21 promotes microglial activation through a p53-dependent transcriptional pathway. We further demonstrate that lincRNA-p21 competitively binds to the miR-181 family and induces microglial activation through the miR-181/PKC-δ pathway. Moreover, PKC-δ induction further increases the expression of p53/lincRNA-p21 and thus forms a circuit. Taken together, our results suggest that p53/lincRNA-p21, together with miR-181/PKC-δ, form a double-negative feedback loop that facilitates sustained microglial activation and the deterioration of neurodegeneration.

MiRNAs are involved in aberrant DNA methylation through regulation of DNA methyltransferases (DNMTs) in the pathogenesis and progression of glioblastomas (GBM). MiR-152-3p was down-expressed in human malignancies, and served as a tumor suppressor. Neurofibromatosis type 2 (NF2) was significantly decreased in GBM tissues with a high level of methylation. However, the link between miR-152-3p, DNMT1 and methylation of NF2 in GBM is not clearly established. This study was conducted to detect the mechanism between miR-152-3p, DNMT1 and NF2 in GBM. The levels of DNMT1 and NF2 expression were studied by qRT-PCR, Western blot, immunofluorescence, and immumohistochemical staining. Methylation in the promoter region of NF2 was detected by methylation-specific PCR and bisulfate genomic sequencing PCR. Cell proliferation was examined by Cell-Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assay, and cell invasion was evaluated by transwell assay. Flow cytomery and Hoechst staining were used to analyze cell apoptosis. A dual luciferase system was used to confirm the relationship between miR-152-3p and DNMT1. Methylation of NF2 and DNMT1 was markedly increased, and miR-152-3p was downregulated in GBM tissues and glioma cells. Both knockdown of DNMT1 and overexpression miR-152-3p showed that demethylation activated the expression of NF2. Furthermore, miR-152-3p directly targeted DNMT1. Both miR-152-3p overexpression and DNMT1 knockdown significantly induced cell apoptosis and inhibited invasive activity. This was also observed after NF2 overexpression. These results indicated that miR-152-3p can inhibit glioma cell proliferation and invasion activities by decreasing DNMT1. The restoration of miR-152-3p may have therapeutic application in the treatment of GBM.