Browsing by Subject "IMMUNITY"

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  • Zhu, Yanshan; Chew, Keng Yih; Wu, Melanie; Karawita, Anjana C.; McCallum, Georgina; Steele, Lauren E.; Yamamoto, Ayaho; Labzin, Larisa I.; Yarlagadda, Tejasri; Khromykh, Alexander A.; Wang, Xiaohui; Sng, Julian D. J.; Stocks, Claudia J.; Xia, Yao; Kollmann, Tobias R.; Martino, David; Joensuu, Merja; Meunier, Frederic A.; Balistreri, Giuseppe; Bielefeldt-Ohmann, Helle; Bowen, Asha C.; Kicic, Anthony; Sly, Peter D.; Spann, Kirsten M.; Short, Kirsty R. (2022)
    Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
  • Kuryk, Lukasz; Moller, Anne-Sophie W.; Garofalo, Mariangela; Cerullo, Vincenzo; Pesonen, Sari; Alemany, Ramon; Jaderberg, Magnus (2018)
    Oncolytic adenoviral immunotherapy activates the innate immune system with subsequent induction of adaptive tumor-specific immune responses to fight cancer. Hence, oncolytic viruses do not only eradicate cancer cells by direct lysis, but also generate antitumor immune response, allowing for long-lasting cancer control and tumor reduction. Their therapeutic effect can be further enhanced by arming the oncolytic adenovirus with costimulatory transgenes and/or coadministration with other antitumor therapies. ONCOS-102 has already been found to be well tolerated and efficacious against some types of treatment-refractory tumors, including mesothelin-positive ovarian cancer (NCT01598129). It induced local and systemic CD8+ T-cell immunity and upregulated programmed death ligand 1. These results strongly advocate the use of ONCOS-102 in combination with other therapeutic strategies in advanced and refractory tumors, especially those expressing the mesothelin antigen. The in vivo work presented herein describes the ability of the oncolytic adenovirus ONCOS-102 to induce mesothelin-specific T-cells after the administration of the virus in bagg albino (BALB/c) mice with mesothelin-positive tumors. We also demonstrate the effectiveness of the interferon-gamma the enzyme-linked immunospot (ELISPOT) assay to detect the induction of T-cells recognizing mesothelin, hexon, and E1A antigens in ONCOS-102treated mesothelioma-bearing BALB/c mice. Thus, the ELISPOT assay could be useful to monitor the progress of therapy with ONCOS-102.
  • Niinistö, Sari; Miettinen, Maija E.; Cuthbertson, David; Honkanen, Jarno; Hakola, Leena; Autio, Reija; Erlund, Iris; Arohonka, Petra; Vuorela, Arja; Härkönen, Taina; Hyöty, Heikki; Krischer, Jeffrey P.; Vaarala, Outi; Knip, Mikael; Virtanen, Suvi M. (2022)
    AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity. MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers. ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations. ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. Trial registry numberNCT00179777
  • The Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank Investigators; COVID Human Genetic Effort; CONSTANCES cohort; 3C-Dijon Study; Cerba HealthCare; Etablissement du Sang study group; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James’s Hospital SARS CoV2 Interest group; French COVID Cohort Study Group; Imagine COVID Group; Bastard, Paul; Gervais, Adrian; Le Voyer, Tom; Seppänen, Mikko R. J. (2021)
    Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.
  • Trouvelot, Sophie; Héloir, Marie-Claire; Poinssot, Benoît; Gauthier, Adrien; Paris, Franck; Guillier, Christelle; Combier, Maud; Tdra, Lucie; Daire, Xavier; Adrian, Marielle (2014)
    Increasing interest is devoted to carbohydrates for their roles in plant immunity. Some of them are elicitors of plant defenses whereas other ones act as signaling molecules in a manner similar to phytohormones. This review first describes the main classes of carbohydrates associated to plant immunity, their role and mode of action. More precisely, the state of the art about perception of “PAMP, MAMP and DAMP type” oligosaccharides is presented and examples of induced defense events are provided. A particular attention is paid to the structure / activity relationships of these compounds. The role of sugars as signaling molecules, especially in plant microbe interactions, is also presented. Secondly, the potentialities and limits of foliar sprays of carbohydrates to stimulate plant immunity for crop protection against diseases are discussed, with focus on the roles of the leaf cuticle and phyllosphere microflora.
  • Cervera-Carrascon, Victor; Quixabeira, Dafne C.A.; Havunen, Riikka; Santos, Joao M.; Kutvonen, Emma; Clubb, James H.A.; Siurala, Mikko; Heiniö, Camilla; Zafar, Sadia; Koivula, Teija; Lumen, Dave; Vaha, Marjo; Garcia-Horsman, Arturo; Airaksinen, Anu J.; Sorsa, Suvi; Anttila, Marjukka; Hukkanen, Veijo; Kanerva, Anna; Hemminki, Akseli (2020)
    Despite some promising results, the majority of patients do not benefit from T-cell therapies, as tumors prevent T-cells from entering the tumor, shut down their activity, or downregulate key antigens. Due to their nature and mechanism of action, oncolytic viruses have features that can help overcome many of the barriers currently facing T-cell therapies of solid tumors. This study aims to understand how four different oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus and reovirus) perform in that task. For that purpose, an immunocompetent in vivo tumor model featuring adoptive tumor-infiltrating lymphocyte (TIL) therapy was used. Tumor growth control (p
  • Kotilainen, Hannele; Lokki, Marja-Liisa; Paakkanen, Riitta; Seppanen, Mikko; Tukiainen, Pentti; Meri, Seppo; Poussa, Tuija; Eskola, Jussi; Valtonen, Ville; Jarvinen, Asko (2014)
  • Kimura, Sachie; Hunter, Kerri; Vaahtera, Lauri; Tran, Cuong; Citterico, Matteo; Vaattovaara, Aleksia; Rokka, Anne; Stolze, Sara Christina; Harzen, Anne; Meißner, Lena; Wilkens, Maya Melina Tabea; Hamann, Thorsten; Toyoga, Masatsugu; Nakagami, Hirofumi; Wrzaczek, Michael (2020)
    Reactive oxygen species (ROS) are important messengers in eukaryotic organisms and their production is tightly controlled. Active extracellular ROS production by NADPH oxidases in plants is triggered by receptor-like protein kinase (RLK)-dependent signaling networks. Here we show that the cysteine-rich RLK CRK2 kinase activity is required for plant growth and CRK2 exists in a preformed complex with the NADPH oxidase RBOHD in Arabidopsis. Functional CRK2 is required for the full elicitor-induced ROS burst and consequently the crk2 mutant is impaired in defense against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Our work demonstrates that CRK2 regulates plant innate immunity. We identified in vitro CRK2-dependent phosphorylation sites in the C-terminal region of RBOHD. Phosphorylation of S703 RBOHD is enhanced upon flg22 treatment and substitution of S703 with alanine reduced ROS production in Arabidopsis. Phylogenetic analysis suggests that phospho-sites in C-terminal region of RBOHD are conserved throughout the plant lineage and between animals and plants. We propose that regulation of NADPH oxidase activity by phosphorylation of the C-terminal region might be an ancient mechanism and that CRK2 is an important element in regulating MAMP-triggered ROS production.
  • Xu, Cheng-Jian; Soderhall, Cilla; Bustamante, Mariona; Baiz, Nour; Gruzieva, Olena; Gehring, Ulrike; Mason, Dan; Chatzi, Leda; Basterrechea, Mikel; Llop, Sabrina; Torrent, Maties; Forastiere, Francesco; Fantini, Maria Pia; Carlsen, Karin C. Lodrup; Haahtela, Tari; Morin, Andreanne; Kerkhof, Marjan; Merid, Simon Kebede; van Rijkom, Bianca; Jankipersadsing, Soesma A.; Bonder, Marc Jan; Ballereau, Stephane; Vermeulen, Cornelis J.; Aguirre-Gamboa, Raul; de Jongste, Johan C.; Smit, Henriette A.; Kumar, Ashish; Pershagen, Goran; Guerra, Stefano; Garcia-Aymerich, Judith; Greco, Dario; Reinius, Lovisa; McEachan, Rosemary R. C.; Azad, Raf; Hovland, Vegard; Mowinckel, Petter; Alenius, Harri; Fyhrquist, Nanna; Lemonnier, Nathanael; Pellet, Johann; Auffray, Charles; van der Vlies, Pieter; van Diemen, Cleo C.; Li, Yang; Wijmenga, Cisca; Netea, Mihai G.; Moffatt, Miriam F.; Cookson, William O. C. M.; Anto, Josep M.; Kere, Juha (2018)
    Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.
  • Brownlie, Demi; Scharenberg, Marlena; Mold, Jeff E.; Hard, Joanna; Kekäläinen, Eliisa; Buggert, Marcus; Nguyen, Son; Wilson, Jennifer N.; Al-Ameri, Mamdoh; Ljunggren, Hans-Gustaf; Marquardt, Nicole; Michaelsson, Jakob (2021)
    Human adaptive-like "memory" CD56(dim)CD16(+) natural killer (NK) cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue residency and tumor homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56(bright)CD16(-) NK cells with hallmarks of tissue residency, including expression of CD49a. Expansions of adaptive-like lung tissue-resident NK (trNK) cells were found to be present independently of adaptive-like CD56(dim)CD16(+) NK cells and to be hyperresponsive toward target cells. Together, our data demonstrate that phenotypically, functionally, and developmentally distinct subsets of adaptive-like NK cells exist in human lung and blood. Given their tissue-related character and hyperresponsiveness, human lung adaptive-like trNK cells might represent a suitable alternative for therapies targeting solid tumors.
  • Renkonen, Jutta; Toppila-Salmi, Sanna; Joenvaara, Sakari; Mattila, Pirkko; Parviainen, Ville; Hagstrom, Jaana; Haglund, Caj; Lehtonen, Mikko; Renkonen, Risto (2015)
    Toll-like receptors (TLRs) are important in barrier homeostasis, but their role in airborne allergies is not fully understood. The aim was to evaluate baseline and allergen-induced expression of TLR proteins in nasal epithelium during allergic rhinitis. Nineteen otherwise healthy non-smoking volunteers both allergic to birch pollen and non-allergic controls were enrolled. We took nasal biopsies before and after off-seasonal intranasal birch pollen or diluent challenge. The expression of epithelial TLR1-7, TLR9-10, and MyD88 proteins was immunohistochemically evaluated from the nasal biopsies. The TLR1-3 and TLR5-10 mRNAs were observed by RNA-microarray. Baseline epithelial expression of TLR proteins was wide and identical in controls and atopics. After off-seasonal intranasal birch pollen challenge, a negative change in the expression score of TLR1 and TLR6 proteins was detected in the atopic group. TLR mRNA expression was not affected by birch pollen challenge. Nasal epithelium seems to express all known TLRs. The mechanisms by which TLR1, and TLR6 proteins could affect pollen allergen transport need further studies.
  • Honkanen, Jarno; Vuorela, Arja; Muthas, Daniel; Orivuori, Laura; Luopajärvi, Kristiina; Tejesvi, Mysore Vishakante Gowda; Lavrinienko, Anton; Pirttilä, Anna Maria; Fogarty, Christopher L.; Härkönen, Taina; Ilonen, Jorma; Ruohtula, Terhi; Knip, Mikael; Koskimäki, Janne J.; Vaarala, Outi (2020)
    Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.
  • Einarsdottir, Elisabet; Hafren, Lena; Leinonen, Eira; Bhutta, Mahmood F.; Kentala, Erna; Kere, Juha; Mattila, Petri S. (2016)
    To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 x 10(-7), OR = 1.59), rs268662 (P = 1.564 x 10(-6), OR = 1.54), and rs4150992 (P = 3.37 x 10(-6), OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 x 10(-8)). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 x 10(-4), OR = 0.72; rs4150992, P = 1.62 x 10(-4), OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM.
  • Qiao, Wanjin; Liu, Fulu; Wan, Xing; Qiao, Yu; Li, Ran; Wu, Zhenzhou; Saris, Per Erik Joakim; Xu, Haijin; Qiao, Mingqiang (2022)
    Lactococcus lactis is a commonly used fermenting bacteria in cheese, beverages and meat products. Due to the lack of simplified chassis strains, it has not been widely used in the fields of synthetic biology. Thus, the construction of lactic acid bacteria chassis strains becomes more and more important. In this study, we performed whole genome sequencing, annotation and analysis of L. lactis N8. Based on the genome analysis, we found that L. lactis N8 contains two large plasmids, and the function prediction of the plasmids shows that some regions are related to carbohydrate transport/metabolism, multi-stress resistance and amino acid uptake. L. lactis N8 contains a total of seven prophage-related fragments and twelve genomic islands. A gene cluster encoding a hybrid NRPS-PKS system that was found in L. lactis N8 reveals that the strain has the potential to synthesize novel secondary metabolites. Furthermore, we have constructed a simplified genome chassis of L. lactis N8 and achieved the largest amount of deletion of L. lactis so far. Taken together, the present study offers further insights into the function and potential role of L. lactis N8 as a model strain of lactic acid bacteria and lays the foundation for its application in the field of synthetic biology.
  • Lorey, Martina B.; Rossi, Katriina; Eklund, Kari; Nyman, Tuula A.; Matikainen, Sampsa (2017)
    Gram-negative bacteria are associated with a wide spectrum of infectious diseases in humans. Inflammasomes are cytosolic protein complexes that are assembled when the cell encounters pathogens or other harmful agents. The non-canonical caspase-4/5 inflammasome is activated by Gram-negative bacteria-derived lipopolysaccharide (LPS) and by endogenous oxidized phospholipids. Protein secretion is a critical component of the innate immune response. Here, we have used label-free quantitative proteomics to characterize global protein secretion in response to non-canonical inflammasome activation upon intracellular LPS recognition in human primary macrophages. Before proteomics, the total secretome was separated into two fractions, enriched extracellular vesicle (EV) fraction and rest-secretome (RS) fraction using size-exclusion centrifugation. We identified 1048 proteins from the EV fraction and 1223 proteins from the RS fraction. From these, 640 were identified from both fractions suggesting that the non-canonical inflammasome activates multiple, partly overlapping protein secretion pathways. We identified several secreted proteins that have a critical role in host response against severe Gram-negative bacterial infection. The soluble secretome (RS fraction) was highly enriched with inflammation-associated proteins upon intracellular LPS recognition. Several ribosomal proteins were highly abundant in the EV fraction upon infection, and our data strongly suggest that secretion of translational machinery and concomitant inhibition of translation are important parts of host response against Gram-negative bacteria sensing caspase-4/5 inflammasome. Intracellular recognition of LPS resulted in the secretion of two metalloproteinases, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and MMP14, in the enriched EV fraction. ADAM10 release was associated with the secretion of TNF, a key inflammatory cytokine, and M-CSF, an important growth factor for myeloid cells probably through ADAM10-dependent membrane shedding of these cytokines. Caspase-4/5 inflammasome activation also resulted in secretion of danger-associated molecules S100A8 and prothymosin- in the enriched EV fraction. Both S100A8 and prothymosin- are ligands for toll-like receptor 4 recognizing extracellular LPS, and they may contribute to endotoxic shock during non-canonical inflammasome activation.
  • Nurmi, Katariina; Kareinen, Ilona; Virkanen, Juhani; Rajamaki, Kristiina; Kouri, Vesa-Petteri; Vaali, Kirsi; Levonen, Anna-Liisa; Fyhrquist, Nanna; Matikainen, Sampsa; Kovanen, Petri T.; Eklund, Kari K. (2017)
    Inflammasomes are intracellular protein platforms, which, upon activation, produce the highly proinflammatory cytokines interleukin (IL)-1 beta and IL-18. Heme, hemin and their degradation products possess significant immunomodulatory functions. Here, we studied whether hemin regulates inflammasome function in macrophages. Both hemin and its derivative, cobalt protoporphyrin (CoPP), significantly reduced IL-1 beta secretion by cultured human primary macrophages, the human monocytic leukemia cell line and also mouse bone marrow-derived and peritoneal macrophages. Intraperitoneal administration of CoPP to mice prior to urate crystal-induced peritonitis alleviated IL-1 beta secretion to the peritoneal cavity. In cultured macrophages, hemin and CoPP inhibited NLRP3 inflammasome assembly by reducing the amount of intracellular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). The reduction of ASC was associated with enhanced autophagosome formation and autophagic flux. Inhibition of autophagy prevented the CoPP-induced depletion of ASC, implying that the depletion was caused by increased autophagy. Our data indicate that hemin functions as an endogenous negative regulator of the NLRP3 inflammasome. The inhibition is mediated via enhanced autophagy that results in increased degradation of ASC. This regulatory mechanism may provide a novel approach for the treatment of inflammasome-related diseases. (C) 2016 S. Karger AG, Basel
  • Kyrklund, Mikael; Kummu, Outi; Kankaanpää, Jari; Akhi, Ramin; Nissinen, Antti; Pauliina Turunen, S.; Pussinen, Pirkko; Wang, Chunguang; Hörkkö, Sohvi (2018)
    Treatment of periodontitis has beneficial effects on systemic inflammation markers that relate to progression of atherosclerosis. We aimed to investigate whether immunization with A hemagglutinin domain (Rgp44) of Porphyromonas gingivalis (Pg), a major etiologic agent of periodontitis, would lead to an antibody response cross-reacting with oxidized low-density lipoprotein (OxLDL) and how it would affect the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/-) mice. The data revealed a prominent IgM but not IgG response to malondialdehyde-acetaldehyde modified LDL (MAA-LDL) after Rgp44 and Pg immunizations, implying that Rgp44/Pgand MAA adducts may share cross-reactive epitopes that prompt IgM antibody production and consequently confer atheroprotection. A significant negative association was observed between atherosclerotic lesion and plasma IgA to Rgp44 in Rgp44 immunized mice, supporting further the anti-atherogenic effect of Rgp44 immunization. Plasma IgA levels to Rgp44 and to Pg in both Rgp44-and Pg-immunized mice were significantly higher than those in saline control, suggesting that IgA to Rgp44 could be a surrogate marker of immunization in Pg-immunized mice. Distinct antibody responses in plasma IgA levels to MAA-LDL, to Pg lipopolysaccharides (Pg-LPS), and to phosphocholine (PCho) were observed after Rgp44 and Pg immunizations, indicating that different immunogenic components between Rpg44 and Pg may behave differently in regard of their roles in the development of atherosclerosis. Immunization with Rgp44 also displayed atheroprotective features in modulation of plaque size through association with plasma levels of IL-1 alpha whereas whole Pg bacteria achieved through regulation of antiinflammatory cytokine levels of IL-5 and IL-10. The present study may contribute to refining therapeutic approaches aiming to modulate immune responses and inflammatory/antiinflammatory processes in atherosclerosis.
  • Udayappan, Shanthadevi D.; Kovatcheva-Datchary, Petia; Bakker, Guido J.; Havik, Stefan R.; Herrema, Hilde; Cani, Patrice D.; Bouter, Kristien E.; Belzer, Clara; Witjes, Julia J.; Vrieze, Anne; de Sonnaville, Noor; Chaplin, Alice; van Raalte, Daniel H.; Aalvink, Steven; Dallinga-Thie, Geesje M.; Heilig, Hans G. H. J.; Bergstrom, Goran; van der Meij, Suzan; van Wagensveld, Bart A.; Hoekstra, Joost B. L.; Holleman, Frits; Stroes, Erik S. G.; Groen, Albert K.; Backhed, Fredrik; de Vos, Willem M.; Nieuwdorp, Max (2017)
    An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.
  • Paasela, Monika; Kolho, Kaija-Leena; Vaarala, Outi; Honkanen, Jarno (2014)