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Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent¹

Emilie Doz^2,*, Nicolas Noulin^2,*,, Elisabeth Boichot, Isabelle Guénon, Lizette Fick, Marc Le Bert^*, Vincent Lagente, Bernhard Ryffel^3,*, Bruno Schnyder^*, Valérie F. J. Quesniaux^* and Isabelle Couillin^3,*

^* University of Orleans and Centre National de la Recherche Scientifique UMR6218, Molecular Immunology and Embryology, Key-Obs S. A., Orleans, France; Institut National de la Santé et de la Recherche Médicale U620, University of Rennes, Rennes, France; and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, Republic of South Africa

Acute cigarette smoke exposure of the airways (two cigarettes twice daily for three days) induces acute inflammation in mice. In this study, we show that airway inflammation is dependent on Toll-like receptor 4 and IL-1R1 signaling. Cigarette smoke induced a significant recruitment of neutrophils in the bronchoalveolar space and pulmonary parenchyma, which was reduced in TLR4-, MyD88-, and IL-1R1-deficient mice. Diminished neutrophil influx was associated with reduced IL-1, IL-6, and keratinocyte-derived chemokine levels and matrix metalloproteinase-9 activity in the bronchoalveolar space. Further, cigarette smoke condensate (CSC) induced a macrophage proinflammatory response in vitro, which was dependent on MyD88, IL-1R1, and TLR4 signaling, but not attributable to LPS. Heat shock protein 70, a known TLR4 agonist, was induced in the airways upon smoke exposure, which probably activates the innate immune system via TLR4/MyD88, resulting in airway inflammation. CSC-activated macrophages released mature IL-1β only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1 and pro-IL-1β implicating cooperation between TLRs and the inflammasome. In conclusion, acute cigarette exposure results in LPS-independent TLR4 activation, leading to IL-1 production and IL-1R1 signaling, which is crucial for cigarette smoke induced inflammation leading to chronic obstructive pulmonary disease with emphysema.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the French Ministère de l’Education Nationale de la Recherche et de la Technologie, Centre National de la Recherche Scientifique, and Association de Recherche sur les Nicotianées. The work was also supported by the Fondation de la Recherche Médicale.

² E.D. and N.N. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Isabelle Couillin and Dr. Bernhard Ryffel, Molecular Immunology and Embryology, Centre National de la Recherche Scientifique UMR6218, Transgenose Institute, 3B rue de la Férollerie 45071 Orleans, France. E-mail addresses: couillin{at}cnrs-orleans.fr and bryffel{at}cnrs-orleans.fr

⁴ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage; MMP, matrix metalloproteinase; Penh, enhanced pause as a sign of respiratory dysfunction; TTBS, Tween 20 Tris Buffer Saline; MPO, myeloperoxidase; BMDM, bone marrow-derived macrophages; CSC, cigarette smoke condensate; 7-AAD, 7-aminoactinomycin D; hsp, heat shock protein; WT, wild type.

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