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SFF-Sentre for fremragende forskn

Centre of Molecular Inflammation Research (CEMIR)

Alternative title: Senter for Molekylær Inflammasjonsforskning

Awarded: NOK 165.1 mill.

The scientific activities at CEMIR have proceeded with very good progress. CEMIR researchers have published more that 600 articles since 2013, several in high quality journals. Some of the most significant discoveries from CEMIR in the period 2013-21 include: Espevik and co-workers published new data in J. Immunol, 2014, on inflammatory mechanisms underlying inflammatory responses induced by cholesterol crystals. Considering these results, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis. Latz, Espevik and co-workers reported in Nature Immunology that the inflammasome adaptor called ASC recruits and activates caspase-1, which induces maturation of the cytokine interleukin 1 beta and pyroptotic cell death. ASC specks are detected in bodily fluids from inflamed tissues, and autoantibodies to ASC specks develop in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication. The paper was regarded as groundbreaking and its theme was displayed on the front page of Nature Immunology in August 2014. The group of Lien published an important paper in PNAS describing new molecular mechanisms of bacteria-induced cell killing. From the data they propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-kB and inflammasome activation, and host resistance after infection with the plague bacteria Yersinia pestis. The theme of this paper was displayed on the front page of the journal in May 2014. In 2015 Flo et al. published in PNAS new mechanisms for how pathogenic mycobacteria can survive inside macrophages. The results showed that the Kelch-like ECH-associated protein 1 (Keap1) is a negative regulator for inflammation responses in M. avium infected human macrophages which can cause increased growth of the bacteria inside these cells. Bjørkøy et al. published a study in Autophagy, 2015, that revealed new mechanisms behind protective effects of marine omega-3 fatty acids against diseases. The group found that these fatty acids induce the production of antioxidants and starts an autophagy response against mis-folded proteins. These mechanisms may be of importance for reduction of diseases caused by formation of protein aggregates. Latz and Espevik published in Sci Transl Med, 2016, that cyclodextrin (CD) inhibited the development of atherosclerosis by reprogramming macrophages. CD increased the metabolism of cholesterol and stimulates LXR-dependent gene expression resulting in secretion of cholesterol and reduced inflammation responses. This work is a clear example of translational research in CEMIR that may have implications for treatment of atherosclerosis. Since 2011 CEMIR researchers have participated in the world biggest genetic study on preeclampsia in the EU project InterPregGen. This work resulted in the discovery of a fetus gene that increases the risk of preeclampsia (Nature Genetics, 2017). In a paper published in Science, 2018, Lien and co-authors revealed new molecular mechanisms that the bacterium Yersinia uses to kill macrophages. During infection, the bacteria will shut off an intracellular kinase called TAK1. When the macrophage senses this, it will initiate an intracellular signalling system that results in cell death. The study opens for new understanding of mechanisms that are initiated in macrophages during infection with a broad spectrum of bacteria. CEMIR-researchers have been working to understand mechanisms for how sepsis and septic shock develop. In 2019 the centre published a large piece of work in Plos Path. that described new mechanisms for how Gram-negative bacteria are phagocytosed and killed by macrophages. Sandvik et al. reported in 2019 in J. Pathol that lipocalin 2/NGAL has an important regulatory role in mucosal repair. In 2020 Flo and coworkers demonstrated in Nature Communications how M. tuberculosis activates the NLRP3 inflammasome system in macrophages with subsequent disruption of the plasma membrane. Standal and co-workers published a paper in Blood in 2020 showing that altered immunoglobulin glycosylation mediate bone loss in multiple myeloma. In a comprehensive work published in Nature Communications, 2021, Oudhoff et al. showed how smooth muscle cells can maintain proper functions of stem cells in the gut and mediate positive effect on repair and regeneration of the gut epithelium. This work was highlighted by the Editor as one of the 50 best papers recently published in the stem cell research field. CEMIR also has an innovation project that has resulted in a publication of a PCT patent application in 2021 (inventors Yurchenko, Husebye, Espevik). It has been shown that the C-terminal end of the immunoreceptor SLAMF1 can strongly inhibit inflammation reactions. These peptides have the potential to be developed into novel drugs for treatment of pathological inflammation.

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English version Inflammation is a host response that is triggered by noxious stimuli arising during infection and tissue injury. A controlled inflammatory response is needed to fight infections and to heal wounds, but can become detrimental if dysregulate d as seen in cardiovascular disease (CVD), inflammatory bowel disease (IBD) and others. The recent discoveries that pattern recognition receptors (PRRs) directly sense inflammatory stimuli and activate innate immune cells have greatly increased our molecu lar understanding of inflammatory diseases. Our principal hypothesis is that some of the clinical manifestations are caused by common underlying inflammatory mechanisms instrumented by PRRs. Through an integrated 10-year program of research and research training in molecular innate immune responses CEMIR will elucidate on how PRRs initiate and regulate inflammatory responses and apply this new knowledge in human disease models of CVD, IBD and bone destruction to identify new diagnostic tools and therapeut ic targets for inflammatory diseases. We propose to identify key vesicle transport components regulating PRR-responses and also to use intracellular pathogens as tools to define the interplay between autophagy and PRR-signaling. In addition we want to dec ipher how cholesterol initiate (crystals) and regulate PRR-signaling, and how the NLRP12 inflammasome relate to non-sterile inflammation and metabolic syndrome. Bringing together in one Centre the expertise on basic PRR responses, intracellular trafficking and autophagy will facilitate innovative research on how these processes are connected in regulating inflammation, and provide significant insight into common underlying mechanisms of inflammatory disorders. The localization of CEMIR in an integrated Un iversity hospital environment will facilitate translational research on human disease models by the clinical research groups using available biobanks from patients with CVD, IBD and multiple myeloma. Norwegian version I immunforsvaret har vi sensorer som gjenkjenner molekyler fra både mikrober og fra skadde celler i kroppen. Aktivering av disse sensorene utløser en inflammasjon (betennelse) som har til hensikt å fjerne mikrober og reparere skadene. Selve inflammasjonsreaksjonen må reguleres nøye. En alt for kraftig reaksjon kan føre til blodforgiftning. Kronisk inflammasjon er koblet til sykdommer som aterosklerose, kreft, overvekt, diabetes type II, Alzheimer's sykdom og inflammatorisk tarmsykdom. Et sentralt spørsmål er hvordan inflammasjon kan være så nært knyttet til mange tilsynelatende forskjellige kroniske sykdommer. CEMIR sitt forskningsprogram har som hypotese at nøkkelen til nye terapeutiske mål for kroniske inflammatoriske sykdommer finnes i de helt tidlige faser av inflammasjonsresponsen hvor sensorer i det medfødte immunforsvaret aktiveres. Målet med CEMIR er å finne ut hvordan sensorer i det medfødte immunforsvaret initierer og regulerer inflammasjonsresponser. Denne nye kunnskapen skal benyttes i sykdomsmodeller for å identifisere nye tera peutiske mål og diagnostiske verktøy for inflammatoriske sykdommer. Gjennom etablering av CEMIR, vil det også bli satt i gang organisert forskerutdanning innen molekylære inflammasjonsresponser. I forskningsprogrammet skal det brukes avanserte molekylære og cellulære avbildningsteknikker, transgene musemodeller, forskjellige cellemodeller for inflammasjonsresponser, og biobankprøver fra personer med kardiovaskulær sykdom, inflammatorisk tarmsykdom og kreft (myelomatose). Senteret skal bygges opp rundt 5 etablerte lokale forskningsgrupper (4 grupper fra Institutt for kreftforskning og molekylærmedisin, NTNU, og en gruppe fra Høyskolen i Sør-Trøndelag). Seks internasjonalt ledende forskere (3 fra USA, en fra Tyskland og to fra Norge) skal rekrutteres til s enteret i professor II stillinger. Terje Espevik er leder, og Trude Helen Flo nestleder for CEMIR. Mer informasjon finnes på senteret sin hjemmeside, http://www.ntnu.edu/web/cemir/cemir

Publications from Cristin

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SFF-Sentre for fremragende forskn