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      CD14 Signaling Restrains Chronic Inflammation through Induction of p38-MAPK/SOCS-Dependent Tolerance

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          Abstract

          Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes.

          Author Summary

          Macrophages express CD14 which partners with Toll-like receptor 2/1 to recognize bacterial lipoproteins such as those of Borrelia burgdorferi, the causative agent of Lyme disease. In vitro evidence demonstrates that blocking CD14 recognition of bacterial components ablates innate host cell inflammatory responses. Similarly, blocking downstream p38 kinase activity dampens the cellular response to these same microbial stimuli. This body of work underpins two well-established paradigms which cite the primacy of CD14 in facilitating TLR recognition of microbes to initiate proinflammatory signaling events and the importance of p38 in augmenting such responses. However, contrary to these paradigms, our prior study using a mouse model of Lyme disease demonstrated an association between CD14 deficiency, increased bacterial burden, and more severe and persistent disease. Herein, we provide a mechanistic explanation for this unanticipated host immune response implicating impaired negative regulation of inflammatory signaling pathways as an underlying cause. Consequent to impaired negative regulation the host becomes “intolerant” of continued exposure to bacteria and thus mounts a perpetual inflammatory response to their presence. An intriguing question raised by these findings is whether individual differences in the severity and clinical course of infection might reflect the susceptibility of the patient's innate immune system to tolerization.

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          Most cited references91

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          A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.

          Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
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            ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity.

            Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. Here we used ASK1-deficient mice to show that ASK1 was selectively required for lipopolysaccharide-induced activation of p38 but not of Jnk or the transcription factor NF-kappaB. ASK1 was required for the induction of proinflammatory cytokines dependent on Toll-like receptor 4 (TLR4) but not TLR2 or other TLRs. Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock. Lipopolysaccharide induced the production of intracellular reactive oxygen species, which was required for the formation of a complex of the adaptor molecule TRAF6 and ASK1 and subsequent activation of the ASK1-p38 pathway. Our data demonstrate that the reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity.
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              CD14 is required for MyD88-independent LPS signaling.

              The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea-mutated mice that showed defective responses to microbial inducers. Macrophages from Heedless homozygotes signaled by the MyD88-dependent pathway in response to rough lipopolysaccharide (LPS) and lipid A, but not in response to smooth LPS. In addition, the Heedless mutation prevented TRAM-TRIF-dependent signaling in response to all LPS chemotypes. Heedless also abolished macrophage responses to vesicular stomatitis virus and substantially inhibited responses to specific ligands for the Toll-like receptor 2 (TLR2)-TLR6 heterodimer. The Heedless phenotype was positionally ascribed to a premature stop codon in Cd14. Our data suggest that the TLR4-MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction. Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                December 2009
                December 2009
                11 December 2009
                : 5
                : 12
                : e1000687
                Affiliations
                [1 ]Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
                [2 ]Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, United States of America
                [3 ]Connecticut Children's Medical Center, Division of Pediatric Infectious Diseases, Hartford, Connecticut, United States of America
                [4 ]Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America
                Medical College of Wisconsin, United States of America
                Author notes
                [¤]

                Current address: Department of Biomedical Sciences, Quinnipiac University, Hamden, Connecticut, United States of America

                Conceived and designed the experiments: JCS JDR TJS. Performed the experiments: BS RLP. Analyzed the data: BS JCS TJS. Contributed reagents/materials/analysis tools: CHE JCS JDR. Wrote the paper: BS TJS.

                Article
                09-PLPA-RA-1339R2
                10.1371/journal.ppat.1000687
                2781632
                20011115
                ecc422a6-6bd2-4e00-bcf1-d5e7ab8e1227
                Sahay et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 7 August 2009
                : 10 November 2009
                Page count
                Pages: 18
                Categories
                Research Article
                Immunology/Cellular Microbiology and Pathogenesis
                Immunology/Immunity to Infections
                Immunology/Immunomodulation
                Immunology/Innate Immunity
                Immunology/Leukocyte Activation
                Immunology/Leukocyte Signaling and Gene Expression

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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