Our results thus show that activation of TLR2 along with TLRs 1 and/or 6 converts microglia into a glioma supportive phenotype.

Most neurological diseases are associated with chronic inflammation initiated by the activation of microglia, which produce cytotoxic and inflammatory factors. Signal transducers and activators of transcription (STATs) are potent regulators of gene expression but contribution of particular STAT to inflammatory gene expression and STAT-dependent transcriptional networks underlying brain inflammation need to be identified. In the present study, we investigated the genomic distribution of Stat binding sites and the role of Stats in the gene expression in lipopolysaccharide (LPS)-activated primary microglial cultures. Integration of chromatin immunoprecipitation-promoter microarray data and transcriptome data revealed novel Stat-target genes including Jmjd3, Ccl5, Ezr, Ifih1, Irf7, Uba7, and Pim1. While knockdown of individual Stat had little effect on the expression of tested genes, knockdown of both Stat1 and Stat3 inhibited the expression of Jmjd3 and inflammatory genes. Transcriptional regulation of Jmjd3 by Stat1 and Stat3 is a novel mechanism crucial for launching inflammatory responses in microglia. The effects of Jmjd3 on inflammatory gene expression were independent of its H3K27me3 demethylase activity. Forced expression of constitutively activated Stat1 and Stat3 induced the expression of Jmjd3, inflammation-related genes, and the production of pro-inflammatory cytokines as potently as lipopolysacharide. Gene set enrichment and gene function analysis revealed categories linked to the inflammatory response in LPS and Stat1C + Stat3C groups. We defined upstream pathways that activate STATs in response to LPS and demonstrated contribution of Tlr4 and Il-6 and interferon-γ signaling. Our findings define novel direct transcriptional targets of Stat1 and Stat3 and highlight their contribution to inflammatory gene expression.Key MessageCombined analysis of genomic Stat occupancy and transcriptome revealed novel Stat target genes in LPS-induced microglia.Jmjd3 transcription factor is a novel transcriptional target of Stat1 and Stat3.Stat1 and Stat3 cooperate with Jmjd3 to induce the expression of pro-inflammatory genes.Constitutively active Stat1 and Stat3 fully mimic the LPS-induced upregulation of inflammatory genes and secretion of cytokines.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-1090-5) contains supplementary material, which is available to authorized users.

Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies.

Small RNAs (sRNAs), an important type of pathogenicity factor, contribute to impairing host immune responses. However, little is known about sRNAs in Puccinia striiformis f. sp. tritici (Pst), one of the most destructive pathogens of wheat (Triticum aestivum L.). Here, we report a novel microRNA-like RNA (milRNA) from Pst termed microRNA-like RNA 1 (Pst-milR1), which suppresses wheat defenses during wheat-Pst interactions. We identified Pst-milR1 as a novel milRNA in Pst. Biological prediction and co-transformation showed that Pst-milR1 takes part in cross-kingdom RNA interference (RNAi) events by binding the wheat pathogenesis-related 2 (PR2) gene. Silencing of the Pst-milR1 precursor resulted in increased wheat resistance to the virulent Pst isolate CYR31. PR2 knock-down plants increased the susceptibility of wheat to the avirulent Pst isolate CYR23. This suggests that Pst-milR1 represses the plant immune response by suppressing the expression of PR2. Taking our findings together, we postulate that Pst-milR1 is an important pathogenicity factor in Pst, which acts as an effector to suppress host immunity. Our results provide significant new insights into the pathogenicity of the stripe rust pathogen.

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