Cutting Edge: MyD88 Controls Phagocyte NADPH Oxidase Function and Killing of Gram-Negative Bacteria

Laroux, F. Stephen; Romero, Xavier; Wetzler, Lee M.; Engel, Pablo; Terhorst, Cox

doi:10.4049/jimmunol.175.9.5596

Cited by 137 publications

(139 citation statements)

References 20 publications

(25 reference statements)

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“…It was shown that NADPH oxidase 4 isozyme directly interacts with TLR4 in human embryonic kidney cells transfected with TLR4, MD-2, and CD14 (51). However, it was shown that MyD88, the downstream component of TLR4, controls NADPH oxidase function in primary macrophages (52). Thus, it is not clear where NADPH oxidase is located in the hierarchical order of TLR4 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Wong

Kwon

Choi

et al. 2009

Journal of Biological Chemistry

471

382

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The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS-or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.

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Section: Discussionmentioning

confidence: 99%

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Wong

Kwon

Choi

et al. 2009

Journal of Biological Chemistry

471

382

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“…Animals having deficient NADPH oxidase activity have impaired NF-B activation and are more susceptible to infection with P. aeruginosa (14). Additional evidence for interaction between TLR signaling and NADPH oxidase activity was provided recently by showing that MyD88 influences NADPH oxidase assembly and NAPDH oxidase-mediated production of superoxides (36). The expression of several NF-B-dependent genes, including IL-1, IL-6, and Nos2, was shown to be down-regulated in MOLF/Ei mice compared with C57BL/6J mice during infection, suggesting that the Ity3 locus may have an impact on the expression of several proinflammatory genes (17).…”

Section: Ncf2 Encodes For P67mentioning

confidence: 91%

Sequencing, Expression, and Functional Analyses Support the Candidacy of Ncf2 in Susceptibility to Salmonella Typhimurium Infection in Wild-Derived Mice

Sancho‐Shimizu

Malo

2006

The Journal of Immunology

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A recessive Salmonella Typhimurium susceptibility locus (immunity to Typhimurium (Ity3) was reported previously on distal mouse chromosome 1 using a cross between C57BL/6J and wild-derived MOLF/Ei mice. This quantitative trait locus is located in a genomic region spanning 84 Mb, rich in candidate genes for which a role in host resistance to Salmonella infection is either known or can be envisioned. In this study, we report the evaluation of neutrophil cytosolic factor 2 (Ncf2) as a candidate Salmonella susceptibility gene for Ity3. Ncf2 encodes p67phox, a subunit of the multiprotein enzyme complex NADPH oxidase, known to be responsible for the generation of superoxides. Congenic mice carrying the Ity3 region from MOLF/Ei, B6.MOLF-Ity/Ity3 were more susceptible to infection compared with control mice heterozygous at Ity3, B6.MOLF-Ity/Ity3MOLF/B6, confirming the existence of a recessive Salmonella susceptibility locus on distal chromosome 1. Spleen Ncf2 expression levels were lower in infected congenic mice homozygous for the MOLF/Ei allele at Ity3 compared with mice heterozygous at Ity3. C57BL/6J and MOLF/Ei Ncf2 sequence comparisons revealed one nonconservative amino acid change (R394Q) in the functional and highly conserved Phox and Bem1 domain of the protein. Functional analysis revealed that the MOLF/Ei allele had reduced PMA- and Salmonella-induced superoxide induction as compared with their wild-type counterparts ex vivo. The R394Q substitution seems to occur on an amino acid involved in electrostatic interactions with p40phox, crucial in its activation. Moreover, a human mutation in the corresponding R395W, resulting in chronic granulatomous disease, is known to lead to reduced superoxide levels. These results support the candidacy of Ncf2 as the gene underlying Ity3.

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“…In contrast, in the present study, we show that SIRL-1 does not affect intracellular ROS production in neutrophils following challenge with opsonized S. aureus. It has been shown that TLR signaling cooperates with FcRs in the killing of intracellular bacteria by promoting assembly and thus activity of the Nox complex (52). Most likely, signaling through SIRL-1 is not able to suppress synchronized FcR and TLR engagement and the resulting synergistic activation of Nox-2 in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

Avondt

Linden

Naccache

et al. 2016

The Journal of Immunology

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In response to microbial invasion, neutrophils release neutrophil extracellular traps (NETs) to trap and kill extracellular microbes. Alternatively, NET formation can result in tissue damage in inflammatory conditions and may perpetuate autoimmune disease. Intervention strategies that are aimed at modifying pathogenic NET formation should ideally preserve other neutrophil antimicrobial functions. We now show that signal inhibitory receptor on leukocytes-1 (SIRL-1) attenuates NET release by human neutrophils in response to distinct triggers, including opsonized Staphylococcus aureus and inflammatory danger signals. NET release has different kinetics depending on the stimulus, and rapid NET formation is independent of NADPH oxidase activity. In line with this, we show that NET release and reactive oxygen species production upon challenge with opsonized S. aureus require different signaling events. Importantly, engagement of SIRL-1 does not affect bacterially induced production of reactive oxygen species, and intracellular bacterial killing by neutrophils remains intact. Thus, our studies define SIRL-1 as an intervention point of benefit to suppress NET formation in disease while preserving intracellular antimicrobial defense.

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Cutting Edge: MyD88 Controls Phagocyte NADPH Oxidase Function and Killing of Gram-Negative Bacteria

Cited by 137 publications

References 20 publications

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Sequencing, Expression, and Functional Analyses Support the Candidacy of Ncf2 in Susceptibility to Salmonella Typhimurium Infection in Wild-Derived Mice

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

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