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Immunology
Interleukin-37: The Effect of Anti-Inflammatory Response in Human Coronary Artery Endothelial Cells.
Feb 10, 2019   Mediators Of Inflammation
Yan X, Xie B, Wu G, Hu J, Wang D, Cai X, Li J
Interleukin-37: The Effect of Anti-Inflammatory Response in Human Coronary Artery Endothelial Cells.
Feb 10, 2019
Mediators Of Inflammation
Interleukin-37 (IL-37) is unique in the IL-1 family since it broadly suppresses innate immunity and elevates in humans with inflammatory and autoimmune diseases. IL-37 shows definite groups and transcripts for human IL37 gene, but it is still not completely understood the effect and mechanisms of inflammatory response in endothelial cells. It is well accepted that endothelial dysfunction caused by inflammation is a key initiating event in atherosclerotic plaque formation, which leads to the occurrence and development of the cardiovascular adverse events in clinical since the inflammatory responses of endothelial cells could induce and enhance the deposition of extensive lipid and the formation of atherosclerotic plaque in the intima. Thus, it is essential to investigate the role and potential mechanisms in endothelial inflammatory response to prevent the formation and development of many cardiovascular diseases including atherosclerosis. So far, the recent studies have revealed that IL-37 is able to inhibit inflammatory response by suppressing the TLR2-NF-κB-ICAM-1 pathway intracellularly in human coronary artery endothelial cells (HCAECs). Further, the role of IL-37 may be related to the IL-18 pathway extracellularly and involved in the adhesion and transmigration of neutrophils in HCAECs.
Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production.
Feb 11, 2019   Autophagy
Wang R, Zhu Y, Lin X, Ren C, Zhao J, Wang F, Gao X, Xiao R, Zhao L, Chen H, Jin M, Ma W, Zhou H
Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production.
Feb 11, 2019
Autophagy
Influenza A virus can evade host innate immune response that is involved in several viral proteins with complicated mechanisms. To date, how influenza A M2 protein modulates the host innate immunity remains unclear. Herein, we showed that M2 protein colocalized and interacted with MAVS (mitochondrial antiviral signaling protein) on mitochondria, and positively regulated MAVS-mediated innate immunity. Further studies revealed that M2 induced reactive oxygen species (ROS) production that was required for activation of macroautophagy/autophagy and enhancement of MAVS signaling pathway. Importantly, the proton channel activity of M2 protein was demonstrated to be essential for ROS production and antagonizing the autophagy pathway to control MAVS aggregation, thereby enhancing MAVS signal activity. In conclusion, our studies provided novel insights into mechanisms of M2 protein in modulating host antiviral immunity and uncovered a new mechanism into biology and pathogenicity of influenza A virus.
Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses.
Feb 13, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Chen X, Alonzo F
Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses.
Feb 13, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
Commensal and pathogenic bacteria hydrolyze host lipid substrates with secreted lipases and phospholipases for nutrient acquisition, colonization, and infection. Bacterial lipase activity on mammalian lipids and phospholipids can promote release of free fatty acids from lipid stores, detoxify antimicrobial lipids, and facilitate membrane dissolution. The gram-positive bacterium Staphylococcus aureus secretes at least two lipases, Sal1 and glycerol ester hydrolase (Geh), with specificities for short- and long-chain fatty acids, respectively, each with roles in the hydrolysis of environmental lipids. In a recent study from our group, we made the unexpected observation that Geh released by S. aureus inhibits activation of innate immune cells. Herein, we investigated the possibility that S. aureus lipases interface with the host immune system to blunt innate immune recognition of the microbe. We found that the Geh lipase, but not other S. aureus lipases, prevents activation of innate cells in culture. Mutation of geh leads to enhancement of proinflammatory cytokine production during infection, increased innate immune activity, and improved clearance of the bacterium in infected tissue. These in vitro and in vivo effects on innate immunity were not due to direct functions of the lipase on mammalian cells, but rather a result of inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern (PAMP) of extracellular gram-positive bacteria, via ester hydrolysis. Altogether, these studies provide insight into an adaptive trait that masks microbial recognition by innate immune cells through targeted inactivation of a broadly conserved PAMP.
Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome.
Feb 13, 2019   MBio
Botto S, Abraham J, Mizuno N, Pryke K, Gall B, Landais I, Streblow DN, Fruh KJ, DeFilippis VR
Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome.
Feb 13, 2019
MBio
Secretion of interleukin-1β (IL-1β) represents a fundamental innate immune response to microbial infection that, at the molecular level, occurs following activation of proteolytic caspases that cleave the immature protein into a secretable form. Human cytomegalovirus (HCMV) is the archetypal betaherpesvirus that is invariably capable of lifelong infection through the activity of numerous virally encoded immune evasion phenotypes. Innate immune pathways responsive to cytoplasmic double-stranded DNA (dsDNA) are known to be activated in response to contact between HCMV and host cells. Here, we used clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) genome editing to demonstrate that the dsDNA receptor absent in melanoma 2 (AIM2) is required for secretion of IL-1β following HCMV infection. Furthermore, dsDNA-responsive innate signaling induced by HCMV infection that leads to activation of the type I interferon response is also shown, unexpectedly, to play a contributory role in IL-1β secretion. Importantly, we also show that rendering virus particles inactive by UV exposure leads to substantially increased IL-1β processing and secretion and that live HCMV can inhibit this, suggesting the virus encodes factors that confer an inhibitory effect on this response. Further examination revealed that ectopic expression of the immediate early (IE) 86-kDa protein (IE86) is actually associated with a block in transcription of the pro-IL-1β gene and, independently, diminishment of the immature protein. Overall, these results reveal two new and distinct phenotypes conferred by the HCMV IE86 protein, as well as an unusual circumstance in which a single herpesviral protein exhibits inhibitory effects on multiple molecular processes within the same innate immune response.IMPORTANCE Persistent infection with HCMV is associated with the operation of diverse evasion phenotypes directed at antiviral immunity. Obstruction of intrinsic and innate immune responses is typically conferred by viral proteins either associated with the viral particle or expressed immediately after entry. In line with this, numerous phenotypes are attributed to the HCMV IE86 protein that involve interference with innate immune processes via transcriptional and protein-directed mechanisms. We describe novel IE86-mediated phenotypes aimed at virus-induced secretion of IL-1β. Intriguingly, while many viruses target the function of the molecular scaffold required for IL-1β maturation to prevent this response, we find that HCMV and IE86 target the IL-1β protein specifically. Moreover, we show that IE86 impairs both the synthesis of the IL-1β transcript and the stability of the immature protein. This indicates an unusual phenomenon in which a single viral protein exhibits two molecularly separate evasion phenotypes directed at a single innate cytokine.
Podocytes and autophagy: A potential therapeutic target in lupus nephritis.
Feb 13, 2019   Autophagy
Zhou XJ, Klionsky DJ, Zhang H
Podocytes and autophagy: A potential therapeutic target in lupus nephritis.
Feb 13, 2019
Autophagy
Recent studies suggest that defects in macroautophagy/autophagy contribute to the pathogenesis of systemic lupus erythamatosus (SLE), especially in adaptive immunity. The occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for establishing the role of autophagy in the pathogenesis of LN, and as a therapy target. In our recent study, we observed that autophagy is activated in LN, especially in podocytes. Based on in vitro assays, many of the most important mediators of the disease-patients' sera, patients' IgG and IFNA/IFN-α-can induce autophagy in both murine and human podocytes, by reactive oxygen species production or MTORC1 inhibition; autophagy activation negatively associates with podocyte injury. With regard to intervention, autophagy activators can protect against podocyte injury, whereas autophagy inhibitors aggravate injury. Taken together, our findings suggest that podocyte autophagy is involved in lupus renal protection and may be a therapeutic target. These data shed new light on the role of rapamycin and autophagy inducers in the treatment of SLE.
A new genomic blueprint of the human gut microbiota.
Feb 16, 2019   Nature Add nature.com free-link Cancel
Almeida A, Mitchell AL, Boland M, Forster SC, Gloor GB, Tarkowska A, Lawley TD, Finn RD
A new genomic blueprint of the human gut microbiota.
Feb 16, 2019
Nature
The composition of the human gut microbiota is linked to health and disease, but knowledge of individual microbial species is needed to decipher their biological roles. Despite extensive culturing and sequencing efforts, the complete bacterial repertoire of the human gut microbiota remains undefined. Here we identify 1,952 uncultured candidate bacterial species by reconstructing 92,143 metagenome-assembled genomes from 11,850 human gut microbiomes. These uncultured genomes substantially expand the known species repertoire of the collective human gut microbiota, with a 281% increase in phylogenetic diversity. Although the newly identified species are less prevalent in well-studied populations compared to reference isolate genomes, they improve classification of understudied African and South American samples by more than 200%. These candidate species encode hundreds of newly identified biosynthetic gene clusters and possess a distinctive functional capacity that might explain their elusive nature. Our work expands the known diversity of uncultured gut bacteria, which provides unprecedented resolution for taxonomic and functional characterization of the intestinal microbiota.
Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase.
Feb 12, 2019   Cell Chemical Biology
König S, Pace S, Pein H, Heinekamp T, Kramer J,   . . . . . .   , Hertweck C, Brakhage AA, Gerstmeier J, Proschak E, Werz O
Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase.
Feb 12, 2019
Cell Chemical Biology
The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4H). Here, we identified gliotoxin as inhibitor of LTA4H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models. Gliotoxin failed to inhibit the formation of other eicosanoids and the aminopeptidase activity of the bifunctional LTA4H. Suppression of LTB4 formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTA4H activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB4 by direct interference with LTA4H thereby impairing neutrophil functions in invasive aspergillosis.
Adaptation to Host-Specific Bacterial Pathogens Drives Rapid Evolution of a Human Innate Immune Receptor.
Feb 12, 2019   Current Biology : CB
Adrian J, Bonsignore P, Hammer S, Frickey T, Hauck CR
Adaptation to Host-Specific Bacterial Pathogens Drives Rapid Evolution of a Human Innate Immune Receptor.
Feb 12, 2019
Current Biology : CB
The selective pressure by infectious agents is a major driving force in the evolution of humans and other mammals. Members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family serve as receptors for bacterial pathogens of the genera Haemophilus, Helicobacter, Neisseria, and Moraxella, which engage CEACAMs via distinct surface adhesins. While microbial attachment to epithelial CEACAMs facilitates host colonization, recognition by CEACAM3, a phagocytic receptor expressed by granulocytes, eliminates CEACAM-binding bacteria. Sequence analysis of primate CEACAM3 orthologs reveals that this innate immune receptor is one of the most rapidly evolving human proteins. In particular, the pathogen-binding extracellular domain of CEACAM3 shows a high degree of non-synonymous versus synonymous nucleotide exchanges, indicating an exceptionally strong positive selection. Using CEACAM3 domains derived from different primates, we find that the amino acid alterations found in CEACAM3 translate into characteristic binding patterns for bacterial adhesins. One such amino acid residue is F62 in human and chimp CEACAM3, which is not present in other primates and which is critical for binding the OMP P1 adhesin of Haemophilus aegyptius. Incorporation of the F62-containing motif into gorilla CEACAM3 results in a gain-of-function phenotype with regard to phagocytosis of H. aegyptius. Moreover, CEACAM3 polymorphisms found in human subpopulations widen the spectrum of recognized bacterial adhesins, suggesting an ongoing multivariate selection acting on this innate immune receptor. The species-specific detection of diverse bacterial adhesins helps to explain the exceptionally fast evolution of CEACAM3 within the primate lineage and provides an example of Red Queen dynamics in the human genome.
The 14-3-3η chaperone protein promotes antiviral innate immunity via facilitating MDA5 oligomerization and intracellular redistribution.
Feb 11, 2019   PLoS Pathogens
Lin JP, Fan YK, Liu HM
The 14-3-3η chaperone protein promotes antiviral innate immunity via facilitating MDA5 oligomerization and intracellular redistribution.
Feb 11, 2019
PLoS Pathogens
MDA5 belongs to the RIG-I-like receptor family and plays a non-redundant role in recognizing cytoplasmic viral RNA to induce the production of type I IFNs. Upon RNA ligand stimulation, we observed the redistribution of MDA5 from the cytosol to mitochondrial membrane fractions. However, the molecular mechanisms of MDA5 activation remain less understood. Here we show that 14-3-3η is an essential accessory protein for MDA5-dependent type I IFN induction. We found that several 14-3-3 isoforms may interact with MDA5 through the CARDs (N-MDA5), but 14-3-3η was the only isoform that could enhance MDA5-dependent IFNβ promoter activities in a dose-dependent manner. Knock-down of 14-3-3η in Huh7 cells impaired and delayed the kinetics of MDA5 oligomerization, which is a critical step for MDA5 activation. Consequently, the MDA5-dependent IFNβ promoter activities as well as IFNβ mRNA expression level were also decreased in the 14-3-3η knocked-down cells. We also demonstrated that 14-3-3η is essential in boosting the activation of MDA5-dependent antiviral innate immunity during viral infections. In conclusion, our results uncover a novel function of 14-3-3η to promote the MDA5-dependent IFNβ induction pathway by reducing the immunostimulatory potential of viral dsRNA within MDA5 activation signaling pathway.
Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis.
Feb 11, 2019   Oncogene
Torres-Hernandez A, Wang W, Nikiforov Y, Tejada K, Torres L,   . . . . . .   , Kurz E, Aykut B, Shadaloey SAA, Leinwand J, Miller G
Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis.
Feb 11, 2019
Oncogene
Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.
Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model.
Feb 11, 2019   Nature Immunology Add nature.com free-link Cancel
Erlich Z, Shlomovitz I, Edry-Botzer L, Cohen H, Frank D, Wang H, Lew AM, Lawlor KE, Zhan Y, Vince JE, Gerlic M
Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model.
Feb 11, 2019
Nature Immunology
Inflammasomes are one of the most important mechanisms for innate immune defense against microbial infection but are also known to drive various inflammatory disorders via processing and release of the cytokine IL-1β. As research into the regulation and effects of inflammasomes in disease has rapidly expanded, a variety of cell types, including dendritic cells (DCs), have been suggested to be inflammasome competent. Here we describe a major fault in the widely used DC-inflammasome model of bone marrow-derived dendritic cells (BMDCs) generated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We found that among GM-CSF bone marrow-derived cell populations, monocyte-derived macrophages, rather than BMDCs, were responsible for inflammasome activation and IL-1β secretion. Therefore, GM-CSF bone marrow-derived cells should not be used to draw conclusions about DC-dependent inflammasome biology, although they remain a useful tool for analysis of inflammasome responses in monocytes-macrophages.
Author Correction: Inflammasome signalling in brain function and neurodegenerative disease.
Feb 11, 2019   Nature Reviews. Neuroscience
Heneka MT, McManus RM, Latz E
Author Correction: Inflammasome signalling in brain function and neurodegenerative disease.
Feb 11, 2019
Nature Reviews. Neuroscience
In the originally published version of this article, the competing interests statement indicated that the authors had no competing interests; however, this statement was incorrect. The statement should have read as follows: 'M.H. receives a consultation fee from IFM Therapeutics, LLC for consultations regarding the pathogenesis and interventional strategies of neurodegenerative disease. E.L. is a scientific co-founder and consultant to IFM Therapeutics. R.M.M. declares no competing interests.' This error has been corrected in the HTML and PDF versions of the article.
Nitration of Wheat Amylase Trypsin Inhibitors Increases Their Innate and Adaptive Immunostimulatory Potential in vitro.
Feb 13, 2019   Frontiers In Immunology
Ziegler K, Neumann J, Liu F, Fröhlich-Nowoisky J, Cremer C, Saloga J, Reinmuth-Selzle K, Pöschl U, Schuppan D, Bellinghausen I, Lucas K
Nitration of Wheat Amylase Trypsin Inhibitors Increases Their Innate and Adaptive Immunostimulatory Potential in vitro.
Feb 13, 2019
Frontiers In Immunology
Amylase trypsin inhibitors (ATI) can be found in all gluten containing cereals and are, therefore, ingredient of basic foods like bread or pasta. In the gut ATI can mediate innate immunity via activation of the Toll-like receptor 4 (TLR4) on immune cells residing in the lamina propria, promoting intestinal, as well as extra-intestinal, inflammation. Inflammatory conditions can induce formation of peroxynitrite (ONOO-) and, thereby, endogenous protein nitration in the body. Moreover, air pollutants like ozone (O3) and nitrogen dioxide (NO2) can cause exogenous protein nitration in the environment. Both reaction pathways may lead to the nitration of ATI. To investigate if and how nitration modulates the immunostimulatory properties of ATI, they were chemically modified by three different methods simulating endogenous and exogenous protein nitration and tested in vitro. Here we show that ATI nitration was achieved by all three methods and lead to increased immune reactions. We found that ATI nitrated by tetranitromethane (TNM) or ONOO- lead to a significantly enhanced TLR4 activation. Furthermore, in human primary immune cells, TNM nitrated ATI induced a significantly higher T cell proliferation and release of Th1 and Th2 cytokines compared to unmodified ATI. Our findings implicate a causative chain between nitration, enhanced TLR4 stimulation, and adaptive immune responses, providing major implications for public health, as nitrated ATI may strongly promote inhalative wheat allergies (baker's asthma), non-celiac wheat sensitivity (NCWS), other allergies, and autoimmune diseases. This underlines the importance of future work analyzing the relationship between endo- and exogenous protein nitration, and the rise in incidence of ATI-related and other food hypersensitivities.
Quantitative Proteomics reveals changes in Vero cells in Response to Porcine Epidemic Diarrhea Virus.
Feb 07, 2019   Journal Of Proteome Research
Ye Y, Zhu J, Ai Q, Wang C, Liao M, Fan H
Quantitative Proteomics reveals changes in Vero cells in Response to Porcine Epidemic Diarrhea Virus.
Feb 07, 2019
Journal Of Proteome Research
Outbreaks of porcine epidemic diarrhea virus (PEDV) have caused significant lethality rates in neonatal piglets, which pose a serious threat to the swine industry worldwide. Commercial vaccines available fail to protect against the emergence of high virulence of PEDV variants. Therefore, the endemic state of PEDV infection in suckling piglets highlights the urgent need for uncovering the molecular determinants of the disease pathogenesis. In this study, Stable Isotope Labeling by Amino acids in Cell culture (SILAC), combined with high performance liquid chromatography (HPLC)/tandem mass spectrometry, was performed to determine proteomic differences between PEDV-infected and mock-infected Vero cells at 18 h post-infection. The SILAC-based approach identified 4508 host cell proteins, of which 120 were significantly up-regulated and 103 were significantly down-regulated at ≥ 95% confidence. Alterations in the expression of selected proteins were verified by western blot. Several signaling metabolic pathways including mevalonate pathway I and superpathway of cholesterol biosynthesis were triggered by the infection of the highly virulent strain, which are linked to host innate immunity. 25-HC, an inhibitor of the mevalonate pathway, exhibited potent antiviral activity against PEDV infection. Meanwhile, cell cycle related function were significantly regulated, which may be likely responsible for viral replication and pathogenicity of PEDV.
14-3-3 Protein of Neospora caninum Modulates Host Cell Innate Immunity Through the Activation of MAPK and NF-κB Pathways.
Feb 13, 2019   Frontiers In Microbiology
Li S, Gong P, Zhang N, Li X, Tai L, Wang X, Yang Z, Yang J, Zhu X, Zhang X, Li J
14-3-3 Protein of Neospora caninum Modulates Host Cell Innate Immunity Through the Activation of MAPK and NF-κB Pathways.
Feb 13, 2019
Frontiers In Microbiology
Neospora caninum is an obligate intracellular apicomplexan parasite, the etiologic agent of neosporosis, and a major cause of reproductive loss in cattle. There is still a lack of effective prevention and treatment measures. The 14-3-3 protein is a widely expressed acidic protein that spontaneously forms dimers within apicomplexan parasites. This protein has been isolated and sequenced in many parasites; however, there are few reports about the N. caninum 14-3-3 protein. Here, we successfully expressed and purified a recombinant fusion protein of Nc14-3-3 (rNc14-3-3) and prepared a polyclonal antibody. Immunofluorescence and immunogold electron microscopy studies of tachyzoites or N. caninum-infected cells suggested that 14-3-3 was localized in the cytosol and the membrane. Western blotting analysis indicated that rNc14-3-3 could be recognized by N. caninum-infected mouse sera, suggesting that 14-3-3 may be an infection-associated antigen that is involved in the host immune response. We demonstrated that rNc14-3-3 induced cytokine expression by activating the MAPK and AKT signaling pathways, and inhibitors of p38, ERK, JNK, and AKT could significantly decrease the production of IL-6, IL-12p40, and TNF-α. In addition, phosphorylated nuclear factor-κB (NF-κB/p65) was observed in wild-type peritoneal macrophages (PMs) treated with rNc14-3-3, and the protein level of NF-κB/p65 was reduced in the cytoplasm but increased correspondingly in the nucleus after 2 h of treatment. These results were also observed in deficient in TLR2-/- PMs. Taken together, our results indicated that the N. caninum 14-3-3 protein can induce effective immune responses and stimulate cytokine expression by activating the MAPK, AKT, and NF-κB signaling pathways but did not dependent TLR2, suggesting that Nc14-3-3 is a novel vaccine candidate against neosporosis.
Efficacy of novel selective NLRP3 inhibitors in human and murine retinal pigment epithelial cells.
Feb 10, 2019   Journal Of Molecular Medicine (Berlin, Germany)
Wang L, Schmidt S, Larsen PP, Meyer JH, Roush WR, Latz E, Holz FG, Krohne TU
Efficacy of novel selective NLRP3 inhibitors in human and murine retinal pigment epithelial cells.
Feb 10, 2019
Journal Of Molecular Medicine (Berlin, Germany)
NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD), and pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells. Inflammasome activation was induced in primary human RPE cells and ARPE-19 cells following priming with IL-1α by different stimuli, including lysosomal membrane permeabilization by leucyl-leucine methyl ester (Leu-Leu-OMe), oxidative damage induced by hydrogen peroxide, lipofuscin-mediated photooxidative damage induced by incubation with 4-hydroxynonenal-modified photoreceptor outer segments and subsequent blue light irradiation, and P2X7 receptor activation by benzoylbenzoyl-ATP. Independent of the applied activation mechanism, treatment with the NLRP3 inhibitors IFM-632, IFM-514, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1β and LDH release. Likewise, inflammasome activation in blue light-irradiated Abca4-/- mouse and Leu-Leu-OMe-treated wild-type mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors. These results indicate that the investigated selective NLRP3 inhibitors are effective in human and murine RPE cells, thus representing promising agents for the future evaluation of inflammasome inhibition as a therapeutic strategy in atrophic AMD. KEY MESSAGES: • NLRP3 inhibitors suppress inflammasome activation in human RPE cells independent of trigger. • Light-induced inflammasome activation in Abca4-/- mouse eye cups is reduced by NLRP3 inhibitors. • Novel selective NLRP3 inhibitors are effective in human and murine RPE cells. • Promising compounds for pharmaceutical intervention in atrophic AMD.
A QM protein from Bombyx mori negatively regulates prophenoloxidase activation and melanization by interacting with Jun protein.
Feb 09, 2019   Insect Molecular Biology
Zhou XS, Chen C, Li TH, Tang JJ, Zhu BJ, Wei GQ, Qian C, Liu CL, Wang L
A QM protein from Bombyx mori negatively regulates prophenoloxidase activation and melanization by interacting with Jun protein.
Feb 09, 2019
Insect Molecular Biology
The QM gene that encodes for the ribosomal protein L10 was firstly identified from human tumor cells as a tumor suppressor. In this study, a QM gene was identified in silkworm Bombyx mori (BmQM) and its immunomodulatory function was explored. BmQM mRNA and protein were highly expressed in the silk gland and fat body, and expressed in all stages of silkworm growth. After challenged with four different microorganisms, the expression levels of BmQM mRNA in fat body or hemocytes were significantly upregulated compared with the control. After knock-down of BmQM gene, the expressions of some immune genes (PGRPS6, Gloverin0, Lysozyme, and Moricin) were affected, and the transcripts of prophenoloxidase1 and prophenoloxidase2, have different degrees of increased. The phenoloxidase activity was significantly reduced when injected the purified recombinant BmQM protein. Recombinant BmQM protein inhibited systemic melanization and suppressed prophenoloxidase activation stimulated by M. luteus, but did not affect phenoloxidase activity. Far Western blotting assays showed that the BmQM protein interacted with silkworm BmJun protein which negatively regulates AP-1 expression. Our results indicated that BmQM protein could affect some immune gene expression and negatively regulate the prophenoloxidase-activating system, and it may play an important role in regulation of the innate immunity in insects. This article is protected by copyright. All rights reserved.
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.
Feb 09, 2019   Neuron
Merlini M, Rafalski VA, Rios Coronado PE, Gill TM, Ellisman M, Muthukumar G, Subramanian KS, Ryu JK, Syme CA, Davalos D, Seeley WW, Mucke L, Nelson RB, Akassoglou K
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.
Feb 09, 2019
Neuron
Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.
Reprogramming of Meiotic Chromatin Architecture during Spermatogenesis.
Feb 08, 2019   Molecular Cell
Wang Y, Wang H, Zhang Y, Du Z, Si W,   . . . . . .   , Li Y, Wang Q, Shi Q, Wu X, Xie W
Reprogramming of Meiotic Chromatin Architecture during Spermatogenesis.
Feb 08, 2019
Molecular Cell
Chromatin organization undergoes drastic reconfiguration during gametogenesis. However, the molecular reprogramming of three-dimensional chromatin structure in this process remains poorly understood for mammals, including primates. Here, we examined three-dimensional chromatin architecture during spermatogenesis in rhesus monkey using low-input Hi-C. Interestingly, we found that topologically associating domains (TADs) undergo dissolution and reestablishment in spermatogenesis. Strikingly, pachytene spermatocytes, where synapsis occurs, are strongly depleted for TADs despite their active transcription state but uniquely show highly refined local compartments that alternate between transcribing and non-transcribing regions (refined-A/B). Importantly, such chromatin organization is conserved in mouse, where it remains largely intact upon transcription inhibition. Instead, it is attenuated in mutant spermatocytes, where the synaptonemal complex failed to be established. Intriguingly, this is accompanied by the restoration of TADs, suggesting that the synaptonemal complex may restrict TADs and promote local compartments. Thus, these data revealed extensive reprogramming of higher-order meiotic chromatin architecture during mammalian gametogenesis.
Inflammasome Inhibition Links IRGM to Innate Immunity.
Feb 08, 2019   Molecular Cell
Nabar NR, Kehrl JH
Inflammasome Inhibition Links IRGM to Innate Immunity.
Feb 08, 2019
Molecular Cell
IRGM is a risk factor for several inflammatory diseases, yet no direct link to immune regulation had been shown. In this issue of Molecular Cell, Mehto et al. (2019) report that IRGM limits NLRP3 inflammasome activation-by both direct inhibition of NLRP3/ASC oligomerization and selective autophagic destruction of NLRP3/ASC.
MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.
Feb 08, 2019   ELife
Xu H, Xu SJ, Xie SJ, Zhang Y, Yang JH, Zhang WQ, Zheng MN, Zhou H, Qu LH
MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.
Feb 08, 2019
ELife
MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling. While STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge about miR-122's function and have important implications for treating hepatitis viruses.
Recent Advances in Pathology: The 2019 Annual Review Issue of the Journal of Pathology.
Feb 08, 2019   The Journal Of Pathology
Herrington CS, Poulsom R, Coates PJ
Recent Advances in Pathology: The 2019 Annual Review Issue of the Journal of Pathology.
Feb 08, 2019
The Journal Of Pathology
In this Annual Review Issue of The Journal of Pathology, we present 15 invited reviews on topical aspects of pathology, ranging from the impacts of the microbiome in human disease through mechanisms of cell death and autophagy to recent advances in immunity and the uses of genomics for understanding, classifying and treating human cancers. Each of the reviews is authored by experts in their fields and our intention is to provide comprehensive updates in specific areas of pathology in which there has been considerable recent progress.
Epigenetic mechanisms mediate the experimental evolution of resistance against parasitic fungi in the greater wax moth Galleria mellonella.
Feb 12, 2019   Scientific Reports
Mukherjee K, Dubovskiy I, Grizanova E, Lehmann R, Vilcinskas A
Epigenetic mechanisms mediate the experimental evolution of resistance against parasitic fungi in the greater wax moth Galleria mellonella.
Feb 12, 2019
Scientific Reports
Recent concepts in evolutionary biology suggest that epigenetic mechanisms can translate environmental selection pressures into heritable changes in phenotype. To determine whether experimental selection for a complex trait in insects involves epigenetic modifications, we carried out a generation-spanning experiment using larvae of the greater wax moth Galleria mellonella as a model host to investigate the role of epigenetics in the heritability of resistance against the parasitic fungus Metarhizium robertsii. We investigated differences in DNA methylation, histone acetylation and microRNA (miRNA) expression between an experimentally resistant population and an unselected, susceptible line, revealing that the survival of G. mellonella larvae infected with M. robertsii correlates with tissue-specific changes in DNA methylation and histone modification and the modulation of genes encoding the corresponding enzymes. We also identified miRNAs differentially expressed between resistant and susceptible larvae and showed that these regulatory molecules target genes encoding proteinases and proteinase inhibitors, as well as genes related to cuticle composition, innate immunity and metabolism. These results support our hypothesis that epigenetic mechanisms facilitate, at least in part, the heritable manifestation of parasite resistance in insects. The reciprocal adaptations underlying host-parasite coevolution therefore extend beyond the genetic level to encompass epigenetic modifications.
Drosophila as a Genetic Model for Hematopoiesis.
Feb 11, 2019   Genetics
Banerjee U, Girard JR, Goins LM, Spratford CM
Drosophila as a Genetic Model for Hematopoiesis.
Feb 11, 2019
Genetics
In this FlyBook chapter, we present a survey of the current literature on the development of the hematopoietic system in Drosophila The Drosophila blood system consists entirely of cells that function in innate immunity, tissue integrity, wound healing, and various forms of stress response, and are therefore functionally similar to myeloid cells in mammals. The primary cell types are specialized for phagocytic, melanization, and encapsulation functions. As in mammalian systems, multiple sites of hematopoiesis are evident in Drosophila and the mechanisms involved in this process employ many of the same molecular strategies that exemplify blood development in humans. Drosophila blood progenitors respond to internal and external stress by coopting developmental pathways that involve both local and systemic signals. An important goal of these Drosophila studies is to develop the tools and mechanisms critical to further our understanding of human hematopoiesis during homeostasis and dysfunction.
Pathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis.
Feb 16, 2019   Nature Communications
Lee HG, Lee JU, Kim DH, Lim S, Kang I, Choi JM
Pathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis.
Feb 16, 2019
Nature Communications
T cells generate antigen-specific immune responses to their cognate antigen as a hallmark of adaptive immunity. Despite the importance of antigen-specific T cells, here we show that antigen non-related, bystander memory-like CD4+ T cells also significantly contribute to autoimmune pathogenesis. Transcriptome analysis demonstrates that interleukin (IL)-1β- and IL-23-prime T cells that express pathogenic TΗ17 signature genes such as RORγt, CCR6, and granulocyte macrophage colony-stimulating factor (GM-CSF). Importantly, when co-transferred with myelin-specific 2D2 TCR-transgenic naive T cells, unrelated OT-II TCR-transgenic memory-like TH17 cells infiltrate the spinal cord and produce IL-17A, interferon (IFN)-γ, and GM-CSF, increasing the susceptibility of the recipients to experimental autoimmune encephalomyelitis in an IL-1 receptor-dependent manner. In humans, IL-1R1high memory CD4+ T cells are major producers of IL-17A and IFN-γ in response to IL-1β and IL-23. Collectively, our findings reveal the innate-like pathogenic function of antigen non-related memory CD4+ T cells, which contributes to the development of autoimmune diseases.

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