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Maelfait J.,Unit of Molecular Signal Transduction in Inflammation
PLoS pathogens | Year: 2012

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.

Maelfait J.,Unit of Molecular Signal Transduction in Inflammation | Maelfait J.,Ghent University | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | Beyaert R.,Ghent University
Microbiology and Molecular Biology Reviews | Year: 2012

Detection of viruses by the innate immune system involves the action of specialized pattern recognition receptors. Intracellular RIG-I receptors sense the presence of viral nucleic acids in infected cells and trigger signaling pathways that lead to the production of proinflammatory and antiviral proteins. Over the past few years, posttranslational modification of RIG-I and downstream signaling proteins by different types of ubiquitination has been found to be a key event in the regulation of RIG-I-induced NF-κB and interferon regulatory factor 3 (IRF3) activation. Multiple ubiquitin ligases, deubiquitinases, and ubiquitin binding scaffold proteins contribute to both positive and negative regulation of the RIG-I-induced antiviral immune response. A better understanding of the function and activity of these proteins might eventually lead to the development of novel therapeutic approaches for management of viral diseases. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

van Loo G.,Unit of Molecular Signal Transduction in Inflammation | van Loo G.,Ghent University | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | Beyaert R.,Ghent University
Arthritis Research and Therapy | Year: 2011

The transcription factor NF-κB plays crucial roles in the regulation of inflammation and mmune responses, and inappropriate NF-κB activity has been linked with many autoimmune and inflammatory diseases, including rheumatoid arthritis. Cells employ a multilayered control system to keep NF-κB signalling in check, including a repertoire of negative feedback regulators ensuring termination of NF-κB responses. Here we will review various negative regulatory mechanisms that have evolved to control NF-κB signalling and which have been implicated in the pathogenesis of rheumatoid arthritis. © 2011 BioMed Central Ltd.

Matmati M.,Unit of Molecular Signal Transduction in Inflammation | Matmati M.,Ghent University | Jacques P.,Ghent University | Maelfait J.,Unit of Molecular Signal Transduction in Inflammation | And 25 more authors.
Nature Genetics | Year: 2011

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-°B signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-°B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies. © 2011 Nature America, Inc. All rights reserved.

Verhelst K.,Unit of Molecular Signal Transduction in Inflammation | Verhelst K.,Ghent University | Carpentier I.,Unit of Molecular Signal Transduction in Inflammation | Carpentier I.,Ghent University | And 2 more authors.
Cytokine and Growth Factor Reviews | Year: 2011

TNF is a multifunctional cytokine that plays a key role in innate immunity by inducing the expression of a variety of genes that are involved in an inflammatory response. TNF-induced NF-κB activation is one of the best studied signaling pathways in mammalian cells and has recently led to a revival of research in the biology of ubiquitin. Many NF-κB signaling proteins are modified by specific ubiquitin ligases with different types of ubiquitin chains that are recognized by other proteins and which determine the outcome of ubiquitination. In addition, specific de-ubiquitinases make the whole process reversible. This review summarizes recent findings that have shaped our current understanding on the role of cytoplasmic ubiquitination events in the regulation of TNF-induced NF-κB signaling. © 2011 Elsevier Ltd.

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