Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages

• Published in: Journal of innate immunity 2015-01, Vol.7 (6), p.572-583
• Main Authors: McClure, Clara, Brudecki, Laura, Yao, Zhi Q., McCall, Charles E., El Gazzar, Mohamed
• Format: Article
• Language: English
• Subjects: Animals; Argonaute Proteins - genetics; Argonaute Proteins - immunology; Cell Line, Tumor; Endopeptidases - genetics; Endopeptidases - immunology; Humans; Immune Tolerance - drug effects; Immune Tolerance - genetics; Interleukin-6 - genetics; Interleukin-6 - immunology; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Research Article; RNA-Binding Proteins - genetics; RNA-Binding Proteins - immunology; Shock, Septic - genetics; Shock, Septic - immunology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 1662-811X; 1662-8128
• DOI: 10.1159/000381915

An anti-inflammatory phenotype with pronounced immunosuppression develops during sepsis, during which time neutrophils and monocytes/macrophages limit their Toll-like receptor 4 responses to bacterial lipopolysaccharide (LPS/endotoxin). We previously reported that during this endotoxin-tolerant state, distinct signaling pathways differentially repress transcription and translation of proinflammatory cytokines such as TNFα and IL-6. Sustained endotoxin tolerance contributes to sepsis mortality. While transcription repression requires chromatin modifications, a translational repressor complex of Argonaute 2 (Ago2) and RNA-binding motif protein 4 (RBM4), which bind the 3′-UTR of TNFα and IL-6 mRNA, limits protein synthesis. Here, we show that Dcp1 supports the assembly of the Ago2 and RBM4 repressor complex into cytoplasmic processing bodies (p-bodies) in endotoxin-tolerant THP-1 human monocytes following stimulation with LPS, resulting in translational repression and limiting protein synthesis. Importantly, this translocation process is reversed by Dcp1 knockdown, which restores TNFα and IL-6 protein levels. We also find this translational repression mechanism in primary macrophages of septic mice. Because p-body formation is a critical step in mRNA translation repression, we conclude that Dcp1 is a major component of the translational repression machinery of endotoxin tolerance and may contribute to sepsis outcome.