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      Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection

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          Influenza A virus (IAV) is a significant cause of life-threatening lower respiratory tract infections in children. Antiviral therapy is the mainstay of treatment, but its effectiveness in this age group has been questioned. In addition, damage inflicted on the lungs by the immune response to the virus may be as important to the development of severe lung injury during IAV infection as the cytotoxic effects of the virus itself. A crucial step in the immune response to IAV is activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the subsequent secretion of the inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The IAV matrix 2 proton channel (M2) has been shown to be an important activator of the NLRP3 inflammasome during IAV infection. We sought to interrupt this ion channel-mediated activation of the NLRP3 inflammasome through inhibition of NLRP3 or the cytokine downstream from its activation, IL-1β. Using our juvenile mouse model of IAV infection, we show that inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, beginning 3 days after infection with IAV, improves survival in juvenile mice. Treatment with MCC950 reduces NLRP3 levels in lung homogenates, decreases IL-18 secretion into the alveolar space, and inhibits NLRP3 inflammasome activation in alveolar macrophages. Importantly, inhibition of the NLRP3 inflammasome with MCC950 does not impair viral clearance. In contrast, inhibition of IL-1β signaling with the IL-1 receptor antagonist, anakinra, is insufficient to protect juvenile mice from IAV. Our findings suggest that targeting the NLRP3 inflammasome in juvenile IAV infection may improve disease outcomes in this age group.

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          Most cited references 39

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          Inflammasomes: mechanism of action, role in disease, and therapeutics.

          The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research.
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            A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

            The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.
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              The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.

              The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family of pattern-recognition molecules mediate host immunity to various pathogenic stimuli. However, in vivo evidence for the involvement of NLR proteins in viral sensing has not been widely investigated and remains controversial. As a test of the physiologic role of the NLR molecule NLRP3 during RNA viral infection, we explored the in vivo role of NLRP3 inflammasome components during influenza virus infection. Mice lacking Nlrp3, Pycard, or caspase-1, but not Nlrc4, exhibited dramatically increased mortality and a reduced immune response after exposure to the influenza virus. Utilizing analogs of dsRNA (poly(I:C)) and ssRNA (ssRNA40), we demonstrated that an NLRP3-mediated response could be activated by RNA species. Mechanistically, NLRP3 inflammasome activation by the influenza virus was dependent on lysosomal maturation and reactive oxygen species (ROS). Inhibition of ROS induction eliminated IL-1beta production in animals during influenza infection. Together, these data place the NLRP3 inflammasome as an essential component in host defense against influenza infection through the sensing of viral RNA.

                Author and article information

                1Department of Pediatrics, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                2Ann & Robert H. Lurie Children’s Hospital of Chicago , Chicago, IL, United States
                3Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                4Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                Author notes

                Edited by: István Vadász, Universities of Giessen and Marburg Lung Center, Germany

                Reviewed by: Bastian Opitz, Charité Universitätsmedizin Berlin, Germany; Ian Christopher Davis, The Ohio State University Columbus, United States

                *Correspondence: Bria M. Coates, b-coates@

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                10 July 2017
                : 8
                Copyright © 2017 Coates, Staricha, Ravindran, Koch, Cheng, Davis, Shumaker and Ridge.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 6, Tables: 1, Equations: 0, References: 39, Pages: 12, Words: 7479
                Funded by: National Institute of Child Health and Human Development 10.13039/100000071
                Award ID: K12HD047349
                Funded by: American Thoracic Society 10.13039/100001465
                Funded by: American Lung Association 10.13039/100002590
                Funded by: Respiratory Health Association 10.13039/100007849
                Funded by: National Institutes of Health 10.13039/100000002
                Original Research


                children, influenza, inflammasome, inflammation, mcc950, acute lung injury


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