Chanzyme TRPM7 Mediates the Ca 2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 1; p. 59
• Main Authors: Schappe, Michael S, Szteyn, Kalina, Stremska, Marta E, Mendu, Suresh K, Downs, Taylor K, Seegren, Philip V, Mahoney, Michelle A, Dixit, Sumeet, Krupa, Julia K, Stipes, Eric J, Rogers, Jason S, Adamson, Samantha E, Leitinger, Norbert, Desai, Bimal N
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 16-01-2018
• Subjects: Animals; Calcium; Calcium - metabolism; Calcium ions; Cell activation; Cell Culture Techniques; Cytokines; Endocytosis; Endocytosis - drug effects; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation; Genotyping Techniques; IL-1β; Immune system; Immunoblotting; Inflammation; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - metabolism; Ion channels; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Macrophages; Macrophages - metabolism; Male; Mice; Neurons; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Patch-Clamp Techniques; Pattern recognition; Peritonitis; Proteins; Real-Time Polymerase Chain Reaction; Receptors; Regulation; Rodents; Sepsis; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription activation; Transient receptor potential proteins; Translocation; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; TRP channel; inflammation; ion channel; TRPM7; toll-like receptor; TLR4; LPS; sepsis; endotoxin
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.11.026

Toll-like receptors (TLRs) sense pathogen-associated molecular patterns to activate the production of inflammatory mediators. TLR4 recognizes lipopolysaccharide (LPS) and drives the secretion of inflammatory cytokines, often contributing to sepsis. We report that transient receptor potential melastatin-like 7 (TRPM7), a non-selective but Ca
-conducting ion channel, mediates the cytosolic Ca
elevations essential for LPS-induced macrophage activation. LPS triggered TRPM7-dependent Ca
elevations essential for TLR4 endocytosis and the subsequent activation of the transcription factor IRF3. In a parallel pathway, the Ca
signaling initiated by TRPM7 was also essential for the nuclear translocation of NFκB. Consequently, TRPM7-deficient macrophages exhibited major deficits in the LPS-induced transcriptional programs in that they failed to produce IL-1β and other key pro-inflammatory cytokines. In accord with these defects, mice with myeloid-specific deletion of Trpm7 are protected from LPS-induced peritonitis. Our study highlights the importance of Ca
signaling in macrophage activation and identifies the ion channel TRPM7 as a central component of TLR4 signaling.