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Immunity. 2018 Jan 16;48(1):59-74.e5. doi: 10.1016/j.immuni.2017.11.026.

Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation.

Author information

1
Pharmacology Department, University of Virginia, Jordan Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
2
Pharmacology Department, University of Virginia, Jordan Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA; Carter Immunology Center, University of Virginia, 345 Crispell Dr. MR-6, Charlottesville, VA 22908, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, 415 Lane Rd, Charlottesville, VA 22908, USA.
3
Pharmacology Department, University of Virginia, Jordan Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA; Carter Immunology Center, University of Virginia, 345 Crispell Dr. MR-6, Charlottesville, VA 22908, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, 415 Lane Rd, Charlottesville, VA 22908, USA. Electronic address: bdesai@virginia.edu.

Abstract

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 Ca2+-conducting ion channel, mediates the cytosolic Ca2+ elevations essential for LPS-induced macrophage activation. LPS triggered TRPM7-dependent Ca2+ elevations essential for TLR4 endocytosis and the subsequent activation of the transcription factor IRF3. In a parallel pathway, the Ca2+ 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 Ca2+ signaling in macrophage activation and identifies the ion channel TRPM7 as a central component of TLR4 signaling.

KEYWORDS:

LPS; TLR4; TRP channel; TRPM7; endotoxin; inflammation; ion channel; sepsis; toll-like receptor

PMID:
29343440
PMCID:
PMC5783319
DOI:
10.1016/j.immuni.2017.11.026
[Indexed for MEDLINE]
Free PMC Article

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