Regulation of RLR-Mediated Antiviral Responses of Human Dendritic Cells by mTOR

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Correlation between Type I Interferon Associated Factors and COVID-19 Severity

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN producing cells, plasmacytoid dendritic cells (pDC) have the ability to rapidly produce waste amounts of type I IFNs. Therefore, their low frequency, dysfunction or decreased capacity to produce type I IFNs might increase the risk of severe viral infections. In accordance with that, declined pDC numbers and delayed or inadequate type I IFN responses could be observed in patients with severe coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to individuals with mild or no symptoms. Thus, besides chronic diseases, all those conditions, which negatively affect the antiviral IFN responses lengthen the list of risk factors for severe COVID-19. In the current review, we would like to briefly discuss the role and dysregulation of pDC/type I IFN axis in COVID-19, and introduce those type I IFN-dependent factors, which account for an increased risk of COVID-19 severity and thus are responsible for the different magnitude of individual immune responses to SARS-CoV-2

Regulatory NLRs Control the RLR-Mediated Type I Interferon and Inflammatory Responses in Human Dendritic Cells

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Szabályozott méretű, illetve nano részecskékkel társított polimerek előállítása és vizsgálata: adhézió, módosítás, deformációs mechanizmusok = Preparation and study of polymers combined with nanoparticles or fillers of controlled particle size: adhesion, modification, deformation mechanisms

A szerződés által finanszírozott kutatás a heterogén polimer rendszerek szerkezet-tulajdonság összefüggéseinek megállapítására irányult. A munka során több anyagrendszer vizsgálatával és különböző problémák megoldásával foglalkoztunk. A legfontosabb eredményeket ebben a periódusban a nanokompozitok és a természetes szállal erősített anyagok, valamint a heterogén rendszerek mikromechanikai deformációs folyamatainak vizsgálata során értük el. Megállapítottuk, hogy a polimer/rétegszilikát nanokompozitok szerkezete bonyolultabb annál, mint amit az irodalomban állítanak. A kompozitok tartalmaznak eredeti szemcséket, duzzadt szilikát részecskéket, egyedi lemezeket és egy szilikát hálószerkezet is kialakulhat bennünk. Egyszerű reológiai módszer javasoltunk az utóbbi kimutatására és egy korábban kidolgozott modellünk segítségével becsültük az exfoliáció mértékét. A rétegszilikát nanokompozitok és a faliszttel erősített kompozitok mikromechanikai folyamatainak részletes vizsgálata megmutatta, hogy gyakran a részecskék törése korlátozza a tulajdonságok további javítását. A mikromechanikai deformációs folyamatok követése lehetővé tette az egyes folyamatok szétválasztását, így megállapítottuk, hogy a határfelületek elválása és a mátrix plasztikus deformációja egymást követően megy végbe. Munkánkban számos fiatal kutató vesz részt és kutatási eredményeink nagy része a gyakorlatban is hasznosul. | The research financed by this contract focused on the determination of structure-property correlations in heterogeneous polymer systems. Several materials and problems were studied during the years. The most important results have been achieved in the study of polymer/layered silicate nanocomposites and wood flour filled polymers, as well as in the investigation of the micromechanical deformation processes of heterogeneous polymers. We found that the structure of polymer/layered silicate nanocomposites is more complicated than claimed in the literature. The composites contain original particles, swollen silicate stacks, individual platelets, and a silicate network structure may also form in them. We proposed a simple rheological method to detect the formation of the latter, and used our simple model developed earlier for the quantitative estimation of the extent of exfoliation. The detailed study of the micromechanical deformation processes occurring in layered silicate nanocomposites and wood flour filled polymers showed that often the fracture of the particles limits the further improvement of composite properties. We could separate individual micromechanical deformations and found that debonding and the plastic deformation of the matrix are consecutive processes. Several students and young scientists take part in the research and a large part of the results is utilized in practice

Focusing on the Cell Type Specific Regulatory Actions of NLRX1

Cells utilize a diverse repertoire of cell surface and intracellular receptors to detect exogenous or endogenous danger signals and even the changes of their microenvironment. However, some cytosolic NOD-like receptors (NLR), including NLRX1, serve more functions than just being general pattern recognition receptors. The dynamic translocation between the cytosol and the mito-chondria allows NLRX1 to interact with many molecules and thereby to control multiple cellular functions. As a regulatory NLR, NLRX1 fine-tunes inflammatory signaling cascades, regulates mi-tochondria-associated functions, and controls metabolism, autophagy and cell death. Nevertheless, literature data are inconsistent and often contradictory regarding its effects on individual cellular functions. One plausible explanation might be that the regulatory effects of NLRX1 are highly cell type specific and the features of NLRX1 mediated regulation might be determined by the unique functional activity or metabolic profile of the given cell type. Here we review the cell type specific actions of NLRX1 with a special focus on cells of the immune system. NLRX1 has already emerged as a potential therapeutic target in numerous immune-related diseases, thus we aim to highlight which regulatory properties of NLRX1 are manifested in disease-associated dominant immune cells that presumably offer promising therapeutic solutions to treat these disorders. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Regulation of type I interferon responses by mitochondria-derived reactive oxygen species in plasmacytoid dendritic cells

Mitochondrial reactive oxygen species (mtROS) generated continuously under physiological conditions have recently emerged as critical players in the regulation of immune signaling pathways. In this study we have investigated the regulation of antiviral signaling by increased mtROS production in plasmacytoid dendritic cells (pDCs), which, as major producers of type I interferons (IFN), are the key coordinators of antiviral immunity. The early phase of type I IFN production in pDCs is mediated by endosomal Toll-like receptors (TLRs), whereas the late phase of IFN response can also be triggered by cytosolic retinoic acid-inducible gene-I (RIG-I), expression of which is induced upon TLR stimulation. Therefore, pDCs provide an ideal model to study the impact of elevated mtROS on the antiviral signaling pathways initiated by receptors with distinct subcellular localization. We found that elevated level of mtROS alone did not change the phenotype and the baseline cytokine profile of resting pDCs. Nevertheless increased mtROS levels in pDCs lowered the TLR9-induced secretion of pro-inflammatory mediators slightly, whereas reduced type I IFN production markedly via blocking phosphorylation of interferon regulatory factor 7 (IRF7), the key transcription factor of the TLR9 signaling pathway. The TLR9-induced expression of RIG-I in pDCs was also negatively regulated by enhanced mtROS production. On the contrary, elevated mtROS significantly augmented the RIG-I-stimulated expression of type I IFNs, as well as the expression of mitochondrial antiviral-signaling (MAVS) protein and the phosphorylation of Akt and IRF3 that are essential components of RIG-I signaling. Collectively, our data suggest that increased mtROS exert diverse immunoregulatory functions in pDCs both in the early and late phase of type I IFN responses depending on which type of viral sensing pathway is stimulated

Interactions Between the NLRP3-Dependent IL-1β and the Type I Interferon Pathways in Human Plasmacytoid Dendritic Cells

Generally, a reciprocal antagonistic interaction exists between the antiviral type I interferon (IFN) and the antibacterial nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)-dependent IL-1β pathways that can significantly shape immune responses. Plasmacytoid dendritic cells (pDCs), as professional type I IFN-producing cells, are the major coordinators of antiviral immunity; however, their NLRP3-dependent IL-1β secretory pathway is poorly studied. Our aim was to determine the functional activity of the IL-1β pathway and its possible interaction with the type I IFN pathway in pDCs. We found that potent nuclear factor-kappa B (NF-κB) inducers promote higher levels of pro-IL-1β during priming compared to those activation signals, which mainly trigger interferon regulatory factor (IRF)-mediated type I IFN production. The generation of cleaved IL-1β requires certain secondary signals in pDCs and IFN-α or type I IFN-inducing viruses inhibit IL-1β production of pDCs, presumably by promoting the expression of various NLRP3 pathway inhibitors. In line with that, we detected significantly lower IL-1β production in pDCs of psoriasis patients with elevated IFN-α levels. Collectively, our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in pDCs; however, it may only prevail under inflammatory conditions, in which the type I IFN pathway is not dominant