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JOURNAL IMMUNOLOGY
LETTERS TO THE EDITOR Comment on “Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent”
I
n their article, Doz et al. (1) investigate the role of TLR4/ MyD88 and IL-1R1/MyD88 signaling in cigarette smoke (CS)-induced pulmonary inflammation to unravel mechanisms involved in the development of chronic obstructive pulmonary disease (COPD). In an acute CS exposure model of 3 days, they demonstrate a reduced CS-induced influx of neutrophils in bronchoalveolar lavage (BAL) fluid in TLR4⫺/⫺, MyD88⫺/⫺, and IL-R1⫺/⫺ mice compared with C57BL/6 controls, as well as reduced IL-1, IL-6, and KC levels and reduced matrix metalloproteinase-9 activity in BAL. In contrast, TLR4⫺/⫺ (C57BL/6J, C57BL/10ScNJ, or C3H/HeJ background) and MyD88⫺/⫺ animals appear to develop spontaneous age-related emphysema, which is not associated with an inflammatory response in BAL or lung tissue (2). We demonstrated (3) that subacute CS exposure for 5 wk in TLR4-defective animals (C3H/HeJ) results in a reduced pulmonary accumulation of neutrophils, lymphocytes, and dendritic cells in BAL as well as lower levels of MCP-1 and TNF-␣ compared with wild-type (C3H/HeOuJ) animals. However, after chronic cigarette smoke exposure for 26 wk TLR4 became of less importance, with only minor differences in pulmonary inflammation between the two strains, similar MCP-1 and TNF-␣ levels in BAL, and similar matrix metalloproteinase-12 expression in the lung. These studies highlight the complexity of the pathogenic mechanisms in COPD and emphysema, because CS-induced pulmonary inflammation is TLR4-dependent in (sub) acute experiments (1) whereas it is TLR4-independent in chronic experiments (3). In conclusion, these papers underscore the importance of both acute and chronic models in unraveling the pathogenesis of COPD. 1
Tania Maes, Ken R. Bracke, Guy F. Joos, and Guy G. Brusselle Department of Respiratory Medicine Ghent University Hospital BlokB, Heymans Institute Ghent, Belgium
1
T.M. is sponsored by the Belgian Interuniversity Attraction Poles Program P6/35.
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References 1. Doz, E., N. Noulin, E. Boichot, I. Gue´non, L. Fick, M. Le Bert, V. Lagente, B. Ryffel, B. Schnyder, V. F. J. Quesniaux, and I. Couillin. 2008. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J. Immunol. 180: 1169 –1178. 2. Zhang, X., P. Shan, G. Jiang, L. Cohn, and P. J. Lee. 2006. Toll-like receptor 4 deficiency causes pulmonary emphysema. J. Clin. Invest. 116: 3050 –3059. 3. Maes, T., K. R. Bracke, K. Y. Vermaelen, I. K. Demedts, G. F. Joos, R. A. Pauwels, and G. G. Brusselle. 2006. Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation. Int. Arch. Allergy Immunol. 141: 354 –368.
Response to Comment on “Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent”
W
e investigated the role of TLR4 and MyD88 signaling in an acute cigarette smoke-induced lung inflammation and found that the heat shock protein 70 is up-regulated and is a likely candidate activating TLR4 leading to lung inflammation (1). These findings agree with those of Maes et al. (2), showing that subacute cigarette smoke exposure in TLR4-defective mice results in a reduced pulmonary inflammation. We extended the study to demonstrate that IL-1 is induced in vitro and in vivo after cigarette smoke exposure and that IL-1R1/MyD88 signaling is critical for the acute inflammatory response (1). Furthermore, the findings by Maes et al. (2) indicate that during chronic cigarette exposure TLR4 signaling is less important and point to other as yet unidentified pathways leading to chronic inflammation and emphysema, which were not investigated. IL-1 induced in vivo after cigarette smoke exposure may contribute to this chronic inflammation and emphysema through IL-1R1/MyD88 signaling. Thus, the demonstration of Maes et al. (2) that beyond TLR4-dependent subacute smoke lung inflammation the development of chronic obstructive pulmonary disease is TLR4 independent raises the important point that the signaling pathways leading to acute or chronic disease may differ. Emilie Doz, Bernhard Ryffel, Vale´rie F. J. Quesniaux, and Isabelle Couillin
Molecular Immunology and Embryology Unite´ Mixe de Recherche 6218 University of Orleans and Centre National de la Recherche Scientifique Orleans, France
References 1. Doz, E., N. Noulin, E. Boichot, I. Gue´non, L. Fick, M. Le Bert, V. Lagente, B. Ryffel, B. Schnyder, V. F. J. Quesniaux, and I. Couillin. 2008. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J. Immunol. 180: 1169 –1178. 2. Maes, T., K. R. Bracke, K. Y. Vermaelen, I. K. Demedts, G. F. Joos, R. A. Pauwels, and G. G. Brusselle. 2006. Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation. Int. Arch. Allergy Immunol. 141: 354 –368.
