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Toll-like Receptor 2 Is Essential for the Sensing of Oxidants during Inflammation

¹ Cardiothoracic Pharmacology, Cardiothoracic and Stem Cell Pharmacology, National Heart and Lung Institute, Imperial College London; ² Department of Infectious Diseases, Imperial College Faculty of Medicine, London, United Kingdom; ³ University of Orleans; and ⁴ Centre National de la Recherche Scientifique, Molecular Immunology and Embryology, Orleans, France

Correspondence and requests for reprints should be addressed to Mark J. Paul-Clark, Ph.D., Cardiothoracic Pharmacology, Cardiothoracic and Stem Cell Pharmacology, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, United Kingdom. E-mail: m.paul-clark{at}imperial.ac.uk

Rationale: The mechanisms by which oxidants are sensed by cells and cause inflammation are not well understood.

Objectives: This study aimed to determine how cells "sense" soluble oxidants and how this is translated into an inflammatory reaction.

Methods: Monocytes, macrophages, or HEK293 cells (stably transfected with human Toll-like receptor [TLR]2, TLR2/1, TLR2/6, or TLR4/MD2-CD14) were used. CXC ligand-8 (CXCL8) levels were measured using ELISA. Phosphorylated IL-1 receptor–associated kinase 1 levels were measured using Western blot. TLR2^–/– and TLR4^–/– mice were challenged with oxidants, and inflammation was measured by monitoring cell infiltration and KC levels.

Measurements and Main Results: Oxidants evoked the release of CXCL8 from monocytes/macrophages; this was abrogated by pretreatment with N-acetylcysteine or binding antibodies to TLR2 and was associated with the rapid phosphorylation of IL-1 receptor–associated kinase 1. Oxidants added to HEK293 cells transfected with TLR2, TLR1/2, or TLR2/6 but not TLR4/MD2-CD14 or control HEK nulls resulted in the release of CXCL8. Oxidant challenge delivered intraperitoneally (2–24 hours) or by inhalation to the lungs (3 days) resulted in a robust inflammation in wild-type mice. TLR2^–/– mice did not respond to oxidant challenge in either model. TLR4^–/– mice responded as wild-type mice to oxidants at 2 hours but as TLR2^–/– mice at later time points.

Conclusions: Oxidant–TLR2 interactions provide a signal that initiates the inflammatory response.

Key Words: Toll-like receptors • inflammation • cigarette smoke • oxidants

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Oxidants play an important role in inflammation and pathology; however, there has been little evidence of how oxidants are sensed and propagate inflammation. What This Study Adds to the Field This study shows that exogenous oxidants are sensed by the Toll-like receptor 2, initiating inflammatory processes in the lungs.