Search

Primary cilia influence cell activity, and thus have a unique role in maintaining cell proliferation and differentiation. In atopic dermatitis (AD) and psoriasis, areas of skin inflammation exhibit dysregulated keratinocyte homeostasis. The role of primary cilia in these conditions remains unclear. The objectives of this study is to elucidate the incidence of primary cilia in skin inflammation and the potential mechanism underlying the dysregulation of keratinocytes. Primary cilia were observed using immunofluorescence staining. Normal skin samples were compared with skin samples from patients with AD or psoriasis in terms of cilia numbers and length. The effect of cytokine stimulation on ciliogenesis in keratinocytes was analysed using a primary keratinocyte culture. IFT88, an important ciliary intraflagellar protein, was blocked in Th2 and Th17 cytokines-stimulated keratinocytes. These effects were analysed with quantitative polymerase chain reaction and Western blot. Significant increases in ciliated cells were observed in AD and psoriasis skin samples compared with normal skin samples. The stimulation of keratinocytes using Th2 and Th17 cytokines modulated the formation of primary cilia. The amount of IFT88 in the primary cilia associated with the phosphorylation of JNK, but not p38, in keratinocytes stimulated with interleukin-13, 17A and 22. An increase of ciliated cells in the epidermis may impair keratinocyte differentiation under stress conditions caused by inflammation in both AD and psoriasis patients., identifier:1600-0625

Bakhtiyor Nosirov,1 Joël Billaud,1 Alexis Vandenbon,2 Diego Diez,3 Edward Wijaya,1 Ken J Ishii,4,5 Shunsuke Teraguchi,3 Daron M Standley1,6 1Systems Immunology Lab, 2Immuno-Genomics Research Unit, 3Quantitative Immunology Research Unit, 4Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Suita, 5Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Osaka, 6Lab of Integrated Biological Information, Institute for Virus Research Kyoto University, Kyoto, Japan Purpose: Evidence suggests that circulating serum microRNAs (miRNAs) might preferentially target immune-related mRNAs. If this were the case, we hypothesized that immune-related mRNAs would have more predicted serum miRNA binding sites than other mRNAs and, reciprocally, that serum miRNAs would have more immune-related mRNA targets than non-serum miRNAs.Materials and methods: We developed a consensus target predictor using the random forest framework and calculated the number of predicted miRNA–mRNA interactions in various subsets of miRNAs (serum, non-serum) and mRNAs (immune related, nonimmune related).Results: Immune-related mRNAs were predicted to be targeted by serum miRNA more than other mRNAs. Moreover, serum miRNAs were predicted to target many more immune-related mRNA targets than non-serum miRNAs; however, these two biases in immune-related mRNAs and serum miRNAs appear to be completely independent.Conclusion: Immune-related mRNAs have more miRNA binding sites in general, not just for serum miRNAs; likewise, serum miRNAs target many more mRNAs than non-serum miRNAs overall, regardless of whether they are immune related or not. Nevertheless, these two independent phenomena result in a significantly larger number of predicted serum miRNA–immune mRNA interactions than would be expected by chance. Keywords: biomarker, posttranscriptional regulation, random forest, target prediction

Purpose: Evidence suggests that circulating serum microRNAs (miRNAs) might preferentially target immune-related mRNAs. If this were the case, we hypothesized that immune-related mRNAs would have more predicted serum miRNA binding sites than other mRNAs and, reciprocally, that serum miRNAs would have more immune-related mRNA targets than non-serum miRNAs., Materials and Methods: We developed a consensus target predictor using the random forest framework and calculated the number of predicted miRNA–mRNA interactions in various subsets of miRNAs (serum, non-serum) and mRNAs (immune related, nonimmune related)., Results: Immune-related mRNAs were predicted to be targeted by serum miRNA more than other mRNAs. Moreover, serum miRNAs were predicted to target many more immune-related mRNA targets than non-serum miRNAs; however, these two biases in immune-related mRNAs and serum miRNAs appear to be completely independent., Conclusion: Immune-related mRNAs have more miRNA binding sites in general, not just for serum miRNAs; likewise, serum miRNAs target many more mRNAs than non-serum miRNAs overall, regardless of whether they are immune related or not. Nevertheless, these two independent phenomena result in a significantly larger number of predicted serum miRNA–immune mRNA interactions than would be expected by chance.

Cerebral malaria is the most severe complication of Plasmodium falciparum infection in humans and the pathogenesis is still unclear. Using the P. berghei ANKA infection model of mice, we investigated a potential involvement of Nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. Nlrp3 mRNA expression was upregulated in brain endothelial cells after exposure to P. berghei ANKA. Although ??-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release of IL-1?? in macrophages through Nlrp3, we did not obtain evidence for a role of IL-1?? in vivo . Nlrp3 knock-out mice displayed a delayed onset of cerebral malaria; however, mice deficient in caspase-1, the adaptor protein ASC or the IL-1 receptor succumbed as WT mice. These results indicate that the role of Nlrp3 in experimental cerebral malaria is independent of the inflammasome and the IL-1 receptor pathway.

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di-guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor kappaB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid-sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di-guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor kappaB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid-sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

The call for second generation malaria vaccines needs not only the identification of novel candidate antigens or adjuvants but also a better understanding of immune responses and the underlying protective processes. Plasmodium parasites have evolved a range of strategies to manipulate the host immune system to guarantee survival and establish parasitism. These immune evasion strategies hamper efforts to develop effective malaria vaccines. In the case of a malaria vaccine targeting the N-terminal domain of P. falciparum serine repeat antigen 5 (SE36), now in clinical trials, we observed reduced responsiveness (lowered immunogenicity) which may be attributed to immune tolerance/immune suppression. Here, immunogenicity data and insights into the immune responses to SE36 antigen from epidemiological studies and clinical trials are summarized. Documenting these observations is important to help identify gaps for SE36 continued development and engender hope that highly effective blood-stage/multi-stage vaccines can be achieved., Palacpac N.M.Q., Ishii K.J., Arisue N., et al. Immune tolerance caused by repeated P. falciparum infection against SE36 malaria vaccine candidate antigen and the resulting limited polymorphism. Parasitology International 99, 102845 (2024); https://doi.org/10.1016/j.parint.2023.102845.

Palacpac N.M.Q., Ishii K.J., Arisue N., et al. Immune tolerance caused by repeated P. falciparum infection against SE36 malaria vaccine candidate antigen and the resulting limited polymorphism. Parasitology International 99, 102845 (2024); https://doi.org/10.1016/j.parint.2023.102845., The call for second generation malaria vaccines needs not only the identification of novel candidate antigens or adjuvants but also a better understanding of immune responses and the underlying protective processes. Plasmodium parasites have evolved a range of strategies to manipulate the host immune system to guarantee survival and establish parasitism. These immune evasion strategies hamper efforts to develop effective malaria vaccines. In the case of a malaria vaccine targeting the N-terminal domain of P. falciparum serine repeat antigen 5 (SE36), now in clinical trials, we observed reduced responsiveness (lowered immunogenicity) which may be attributed to immune tolerance/immune suppression. Here, immunogenicity data and insights into the immune responses to SE36 antigen from epidemiological studies and clinical trials are summarized. Documenting these observations is important to help identify gaps for SE36 continued development and engender hope that highly effective blood-stage/multi-stage vaccines can be achieved.