Abstract
The cytosolic sensors Nod1 and Nod2 and Toll-like receptors (TLRs) activate defense signaling pathways in response to microbial stimuli. However, the role of Nod1 and Nod2 and their interplay with TLRs during systemic bacterial infection remains poorly understood. Here, we report that macrophages or mice made insensitive to TLRs by previous exposure to microbial ligands remained responsive to Nod1 and Nod2 stimulation. Furthermore, Nod1- and Nod2-mediated signaling and gene expression are enhanced in TLR-tolerant macrophages. Further analyses revealed that innate immune responses induced by bacterial infection relied on Nod1 and Nod2 and their adaptor RICK in macrophages pretreated with TLR ligands but not in naive macrophages. In addition, bacterial clearance upon systemic infection with L. monocytogenes was critically dependent on Nod1 and Nod2 when mice were previously stimulated with lipopolysaccharide or E. coli. Thus, Nod1 and Nod2 are important for microbial recognition and host defense after TLR stimulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylmuramyl-Alanyl-Isoglutamine / immunology
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Animals
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Cytokines / immunology
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Cytokines / metabolism
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Cytosol / immunology
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Cytosol / metabolism
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Escherichia coli / immunology
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Intracellular Signaling Peptides and Proteins
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Ligands
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Lipopolysaccharides / immunology
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Listeria monocytogenes / immunology
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Listeriosis / immunology*
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Macrophage Activation
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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Nod1 Signaling Adaptor Protein / immunology
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Nod1 Signaling Adaptor Protein / metabolism*
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Nod2 Signaling Adaptor Protein / immunology
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Nod2 Signaling Adaptor Protein / metabolism*
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism*
Substances
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Ligands
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Lipopolysaccharides
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NF-kappa B
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Nod1 Signaling Adaptor Protein
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Nod2 Signaling Adaptor Protein
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Toll-Like Receptors
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Acetylmuramyl-Alanyl-Isoglutamine
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk2 protein, mouse
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Mitogen-Activated Protein Kinases