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¹ Division of Pulmonary, Allergy and Critical Care Medicine, ² Department of Cell Biology and Physiology, and ³ Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
⁴ Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520
⁵ National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
⁶ Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama-shi 700-8558, Japan
⁷ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109

CORRESPONDENCE Augustine M.K. Choi: choiam{at}upmc.edu

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 gp91^phox-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 gp91^phox-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91^phox. Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase–dependent ROS generation.

Abbreviations used: CO, carbon monoxide; CTx, cholera toxin; DPI, diphenylene iodonium; GM1, glycosphingolipid 1; HO, heme oxygenase; IP-10, IFN-–inducible protein 10; IRF-3, IFN regulatory factor 3; MAPK, mitogen-activated protein kinase; MßCD, methyl-ß-cyclodextrin; MDC, monodansylcadaverine; NAC, N-acetyl-L-cysteine; PAMP, pathogen-associated molecular pattern; poly(I:C), polyinosine-polycytidylic acid; RANTES, regulated upon activation, normal T expressed, and presumably secreted; ROS, reactive oxygen species; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor; TRIF, TIR domain–containing adaptor-inducing IFN-ß.

K. Nakahira and H.P. Kim contributed equally to this work.

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