Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts

Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor...

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Main Authors:	Nakahira, Kiichi, Kim, Hong Pyo, Geng, Xue Hui, Nakao, Atsunori, Wang, Xue, Murase, Noriko, Drain, Peter F., Wang, Xiaomei, Sasidhar, Madhu, Nabel, Elizabeth G., Takahashi, Toru, Lukacs, Nicholas W., Ryter, Stefan W., Morita, Kiyoshi, Choi, Augustine M.K.
Format:	Online
Language:	English
Published:	The Rockefeller University Press 2006
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118097/

id	pubmed-2118097
recordtype	oai_dc
spelling	pubmed-21180972007-12-13 Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts Nakahira, Kiichi Kim, Hong Pyo Geng, Xue Hui Nakao, Atsunori Wang, Xue Murase, Noriko Drain, Peter F. Wang, Xiaomei Sasidhar, Madhu Nabel, Elizabeth G. Takahashi, Toru Lukacs, Nicholas W. Ryter, Stefan W. Morita, Kiyoshi Choi, Augustine M.K. Articles Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91phox-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91phox-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91phox. Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase–dependent ROS generation. The Rockefeller University Press 2006-10-02 /pmc/articles/PMC2118097/ /pubmed/17000866 http://dx.doi.org/10.1084/jem.20060845 Text en Copyright © 2006, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Nakahira, Kiichi Kim, Hong Pyo Geng, Xue Hui Nakao, Atsunori Wang, Xue Murase, Noriko Drain, Peter F. Wang, Xiaomei Sasidhar, Madhu Nabel, Elizabeth G. Takahashi, Toru Lukacs, Nicholas W. Ryter, Stefan W. Morita, Kiyoshi Choi, Augustine M.K.
spellingShingle	Nakahira, Kiichi Kim, Hong Pyo Geng, Xue Hui Nakao, Atsunori Wang, Xue Murase, Noriko Drain, Peter F. Wang, Xiaomei Sasidhar, Madhu Nabel, Elizabeth G. Takahashi, Toru Lukacs, Nicholas W. Ryter, Stefan W. Morita, Kiyoshi Choi, Augustine M.K. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
author_facet	Nakahira, Kiichi Kim, Hong Pyo Geng, Xue Hui Nakao, Atsunori Wang, Xue Murase, Noriko Drain, Peter F. Wang, Xiaomei Sasidhar, Madhu Nabel, Elizabeth G. Takahashi, Toru Lukacs, Nicholas W. Ryter, Stefan W. Morita, Kiyoshi Choi, Augustine M.K.
author_sort	Nakahira, Kiichi
title	Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
title_short	Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
title_full	Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
title_fullStr	Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
title_full_unstemmed	Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
title_sort	carbon monoxide differentially inhibits tlr signaling pathways by regulating ros-induced trafficking of tlrs to lipid rafts
description	Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91phox-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91phox-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91phox. Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase–dependent ROS generation.
publisher	The Rockefeller University Press
publishDate	2006
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118097/
_version_	1611414559557419008

Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts

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