IL-26 inhibits hepatitis C virus replication in hepatocytes

Publisher Copyright: © 2021 European Association for the Study of the LiverBackground & Aims: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. Methods: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. Results: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. Conclusions: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. Lay summary: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.Peer reviewe

IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense

Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin

Analysis of the antiviral properties of the interleukin-26

L’interleukine 26 (IL-26) a initialement été décrite comme une molécule surexprimée par des lymphocytes humains transformés par un virus. L’IL-26 a ensuite été classée comme cytokine pro-inflammatoire en raison de sa capacité à induire la production de cytokines par les cellules myéloïdes et épithéliales. Toutefois, ses fonctions biologiques restent méconnues, notamment en raison de l’absence d’orthologue chez le rat et la souris. Le laboratoire avait précédemment rapporté que l’IL-26 est surexprimée chez les patients présentant une inflammation hépatique associée à une infection chronique par le virus de l’hépatite C (HCV) et qu’elle participe à l’immunité antivirale, notamment en conférant aux cellules NK la capacité de tuer des hépatocytes infectés par le virus. Les résultats montraient également que l’IL-26 s’accumule dans les hépatocytes infectés en l’absence d’expression du transcrit. Cette observation, suggérant un rôle non conventionnel pour une cytokine associé à une localisation inhabituelle, a constitué la base de ce projet de recherche. Utilisant un modèle original de réplication du virus HCV in vitro, nos travaux montrent que l’IL-26 protège les hépatocytes de l’infection par HCV en inhibant la réplication de l’ARN viral. Cette propriété repose notamment sur la capacité de l’IL-26 à se lier à l’ARN viral. Ces données identifient l’IL-26 comme un nouvel acteur de l’arsenal antiviral, agissant notamment en inhibant la réplication du virus HCV, et suggèrent que cette molécule peut être classée dans la famille des kinocidines.Initially identified as a molecule over expressed in virus-transformed human T cells, IL-26 has been classified as a pro inflammatory cytokine due to its capacity to induce inflammatory cytokines production by myeloid and epithelial cells. Nevertheless, its biological functions remain largely unknown, in part because of its absence of orthologs in rat and mouse.Our team has previously reported that IL-26, overexpressed in HCV-infected patients, activates NK cells, rendering them able to kill HCV-infected hepatocytes. Results also showed that IL-26 accumulates in hepatocytes of HCV-infected patients, a localization that is not usual for a cytokine. This observation led us to evaluate whether IL-26 may exhibit non-conventional properties. In this study, we demonstrate that IL-26 protects in vitro hepatocytes from HCV infection. Confocal microscopy revealed that IL-26 colocalizes with viral dsRNA. This direct antiviral activity appears to rely on the capacity of IL-26 to bind to viral RNA and to inhibit its replication. Moreover, we investigated the capacity that IL-26 complexed to viral RNA could trigger an antiviral response by immune cells. Collectively, results show that IL-26 may have a manifold protective role during HCV infection: (i) an indirect role via its capacity to confer NK cell the capacity to kill HCV-infected cells, (ii) a direct role through its ability to inhibit viral replication, and (iii) a stimulatory role by rendering viral DNA inflammatory

Analyse des propriétés antivirales de l’interleukine-26

Initially identified as a molecule over expressed in virus-transformed human T cells, IL-26 has been classified as a pro inflammatory cytokine due to its capacity to induce inflammatory cytokines production by myeloid and epithelial cells. Nevertheless, its biological functions remain largely unknown, in part because of its absence of orthologs in rat and mouse.Our team has previously reported that IL-26, overexpressed in HCV-infected patients, activates NK cells, rendering them able to kill HCV-infected hepatocytes. Results also showed that IL-26 accumulates in hepatocytes of HCV-infected patients, a localization that is not usual for a cytokine. This observation led us to evaluate whether IL-26 may exhibit non-conventional properties. In this study, we demonstrate that IL-26 protects in vitro hepatocytes from HCV infection. Confocal microscopy revealed that IL-26 colocalizes with viral dsRNA. This direct antiviral activity appears to rely on the capacity of IL-26 to bind to viral RNA and to inhibit its replication. Moreover, we investigated the capacity that IL-26 complexed to viral RNA could trigger an antiviral response by immune cells. Collectively, results show that IL-26 may have a manifold protective role during HCV infection: (i) an indirect role via its capacity to confer NK cell the capacity to kill HCV-infected cells, (ii) a direct role through its ability to inhibit viral replication, and (iii) a stimulatory role by rendering viral DNA inflammatory.L’interleukine 26 (IL-26) a initialement été décrite comme une molécule surexprimée par des lymphocytes humains transformés par un virus. L’IL-26 a ensuite été classée comme cytokine pro-inflammatoire en raison de sa capacité à induire la production de cytokines par les cellules myéloïdes et épithéliales. Toutefois, ses fonctions biologiques restent méconnues, notamment en raison de l’absence d’orthologue chez le rat et la souris. Le laboratoire avait précédemment rapporté que l’IL-26 est surexprimée chez les patients présentant une inflammation hépatique associée à une infection chronique par le virus de l’hépatite C (HCV) et qu’elle participe à l’immunité antivirale, notamment en conférant aux cellules NK la capacité de tuer des hépatocytes infectés par le virus. Les résultats montraient également que l’IL-26 s’accumule dans les hépatocytes infectés en l’absence d’expression du transcrit. Cette observation, suggérant un rôle non conventionnel pour une cytokine associé à une localisation inhabituelle, a constitué la base de ce projet de recherche. Utilisant un modèle original de réplication du virus HCV in vitro, nos travaux montrent que l’IL-26 protège les hépatocytes de l’infection par HCV en inhibant la réplication de l’ARN viral. Cette propriété repose notamment sur la capacité de l’IL-26 à se lier à l’ARN viral. Ces données identifient l’IL-26 comme un nouvel acteur de l’arsenal antiviral, agissant notamment en inhibant la réplication du virus HCV, et suggèrent que cette molécule peut être classée dans la famille des kinocidines

IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense

International audienceInterleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin. Cytokines are a class of signaling molecules expressed by many cell types, and especially those of the immune system. They are classified in seven major families: the type I cytokine, the type II cytokine (1), the IL-1 (2), and the TGF-β (3) families, the TNF superfamily (4), the receptor tyrosine kinase cytokine family (5), and the chemokine family (6). Although exhibiting pleiotropic properties, they are pivotal regulators of innate and adaptive immune defenses, inflammation, and hematopoiesis. The term "interleukin" (IL) originally refers to a group of cytokines expressed by leukocytes. To date, interleukins have been reported expressed by a wide variety of immune and non-immune cells and exhibit a large panel of properties (e.g., affecting proliferation, activation, differentiation, maturation, migration, and adhesion). Although agonist/antagonist activities and redundancy make any classification particularly complicated, different classifications have been proposed based on their functions, receptor usage or structure. As an example, a functional classification distinguishes eight subgroups of interleukins (IL-1, common γ chain receptor cytokine, cytokines of type 2 immune responses, interleukins with chemokine activity, the IL-10, IL-12, and IL-17 families and, others) (7). A structure-based classification has been also proposed, dividing interleukins into four major groups: IL-1-like cytokines, class I helical cytokines (IL-4-, IL-6-, and IL-12-like ILs, common γ chain receptor cytokines), class II helical cytokines (IL-10-and IL-28-like molecules) and the IL17-like cytokines (8)

Functionalization of phosphocalcic bioceramics for bone repair applications

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A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity

International audienceMemory and long term potentiation require de novo protein synthesis. A key regulator of this process is mTORC1, a complex comprising the mTOR kinase. Growth factors activate mTORC1 via a pathway involving PI3-kinase, Akt, the TSC complex and the GTPase Rheb. In non-neuronal cells, translocation of mTORC1 to late endocytic compartments (LEs), where Rheb is enriched, is triggered by amino acids. However, the regulation of mTORC1 in neurons remains unclear. In mouse hippocampal neurons, we observed that BDNF and treatments activating NMDA receptors trigger a robust increase in mTORC1 activity. NMDA receptors activation induced a significant recruitment of mTOR onto lysosomes even in the absence of external amino acids, whereas mTORC1 was evenly distributed in neurons under resting conditions. NMDA receptor-induced mTOR translocation to LEs was partly dependent on the BDNF receptor TrkB, suggesting that BDNF contributes to the effect of NMDA receptors on mTORC1 translocation. In addition, the combination of Rheb overexpression and artificial mTORC1 targeting to LEs by means of a modified component of mTORC1 fused with a LE-targeting motif strongly activated mTOR. To gain spatial and temporal control over mTOR localization, we designed an optogenetic module based on light-sensitive dimerizers able to recruit mTOR on LEs. In cells expressing this optogenetic tool, mTOR was translocated to LEs upon photoactivation. In the absence of growth factor, this was not sufficient to activate mTORC1. In contrast, mTORC1 was potently activated by a combination of BDNF and photoactivation. The data demonstrate that two important triggers of synaptic plasticity, BDNF and NMDA receptors, synergistically power the two arms of the mTORC1 activation mechanism, i.e., mTORC1 translocation to LEs and Rheb activation. Moreover, they unmask a functional link between NMDA receptors and mTORC1 that could underlie the changes in the synaptic proteome associated with long-lasting changes in synaptic strength

IL-26 Confers Proinflammatory Properties to Extracellular DNA

International audienceIn physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds ton genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10 based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipatic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion Il-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation

Serum Interleukin-26 Is a New Biomarker for Disease Activity Assessment in Systemic Lupus Erythematosus

International audienceObjective Interleukin-26 (IL-26) has a unique ability to activate innate immune cells due to its binding to circulating double-stranded DNA. High levels of IL-26 have been reported in patients with chronic inflammation. We aimed to investigate IL-26 levels in patients with systemic lupus erythematosus (SLE). Methods IL-26 serum levels were quantified by ELISA for 47 healthy controls and 109 SLE patients previously enrolled in the PLUS study. Performance of IL-26 levels and classical markers (autoantibodies or complement consumption) to identify an active SLE disease (SLE disease activity index (SLEDAI) score > 4) were compared. Results IL-26 levels were significantly higher in SLE patients than in controls (4.04 ± 11.66 and 0.74 ± 2.02 ng/mL; p = 0.005). IL-26 levels were also significantly higher in patients with active disease than those with inactive disease (33.08 ± 21.06 vs 1.10 ± 3.80 ng/mL, p < 0.0001). IL-26 levels correlated with SLEDAI score and the urine protein to creatinine ratio (uPCR) (p < 0.001). Patients with high IL-26 levels had higher SLEDAI score, anti-DNA antibodies levels, and uPCR (p < 0.05). They presented more frequently with C3 or C4 complement consumption. Lastly, IL-26 showed stronger performance than classical markers (complement consumption or autoantibodies) for active disease identification. Conclusions Our results suggest that, in addition to classical SLE serological markers, the measurement of IL-26 levels may be a useful biomarker for active disease identification in SLE patients

IL-26 inhibits hepatitis C virus replication in hepatocytes

Publisher Copyright: © 2021 European Association for the Study of the LiverBackground & Aims: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. Methods: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. Results: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. Conclusions: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. Lay summary: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.Peer reviewe