Abstract
Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16(+)) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R-associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16(+) monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / immunology
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Adult
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Animals
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Endotoxins / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology*
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Humans
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Interferons / genetics
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Interferons / immunology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Mice
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Mice, Inbred C57BL
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Middle Aged
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Monocytes / immunology
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Monocytes / metabolism*
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Monocytes / pathology
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Primary Cell Culture
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / immunology
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RNA, Small Interfering / genetics
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Receptors, IgG / genetics*
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Receptors, IgG / immunology
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / immunology
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Sepsis / genetics
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Sepsis / immunology*
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Sepsis / pathology
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Syk Kinase
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Transfection
Substances
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Adaptor Proteins, Vesicular Transport
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Endotoxins
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Intracellular Signaling Peptides and Proteins
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Myeloid Differentiation Factor 88
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RNA, Small Interfering
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Receptors, IgG
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STAT1 Transcription Factor
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TICAM1 protein, human
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TLR4 protein, human
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Toll-Like Receptor 4
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Interferons
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse