Abstract
The recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is pivotal in both innate and adaptive immune responses. Here we demonstrate that deletion of Lgr4/Gpr48 (G-protein-coupled receptor 48), a seven-transmembrane glycoprotein hormone receptor, potentiates TLR2/4-associated cytokine production and attenuates mouse resistance to septic shock. The expression of CD14, a co-receptor for TLR2/4-associated pathogen-associated molecular patterns, is increased significantly in Lgr4-deficient macrophages, which is consistent with the increased immune response, whereas the binding activity of cAMP-response element-binding protein is decreased significantly in Lgr4-deficient macrophages, which up-regulate the expression of CD14 at the transcriptional level. Together, our data demonstrate that Lgr4/Gpr48 plays a critical role in modulating the TLR2/4 signaling pathway and represents a useful therapeutic approach of targeting Lgr4/Gpr48 in TLR2/4-associated septic shock and autoimmune diseases.
Keywords:
CD14; CREB; G-protein-coupled Receptors (GPCRs); Lgr4; Pathogen-associated Molecular Pattern (PAMP); Sepsis; Toll-like Receptors (TLR).
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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Animals
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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Autoimmune Diseases / therapy
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Cell Line
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Humans
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Immunity, Innate / physiology*
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Lipopolysaccharide Receptors / biosynthesis*
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Lipopolysaccharide Receptors / genetics
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Lipopolysaccharide Receptors / immunology
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Macrophages / cytology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / immunology
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Receptors, G-Protein-Coupled / metabolism*
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Shock, Septic / genetics
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Shock, Septic / immunology
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Shock, Septic / metabolism
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Shock, Septic / therapy
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Signal Transduction / physiology
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism*
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Up-Regulation / physiology*
Substances
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LGR4 protein, human
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LGR4 protein, mouse
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Lipopolysaccharide Receptors
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Receptors, G-Protein-Coupled
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TLR2 protein, human
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TLR4 protein, human
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4