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Morphine Induces Defects in Early Response of Alveolar Macrophages to Streptococcus pneumoniae by Modulating TLR9-NF-B Signaling¹

Jinghua Wang^2,3,*, Roderick A. Barke, Richard Charboneau, Reto Schwendener and Sabita Roy^2,*,

^* Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455; Department of Surgery, Veterans Affairs Medical Center, Minneapolis, MN 55417; and Laboratory of Liposome Research, Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

Resident alveolar macrophages and respiratory epithelium constitutes the first line of defense against invading lung pneumococci. Results from our study showed that increased mortality and bacterial outgrowth and dissemination seen in morphine-treated mice were further exaggerated following depletion of alveolar macrophages with liposomal clodronate. Using an in vitro alveolar macrophages and lung epithelial cells infection model, we show significant release of MIP-2 from alveolar macrophages, but not from lung epithelial cells, following 4 h of exposure of cells to pneumococci infection. Morphine treatment reduced MIP-2 release in pneumococci stimulated alveolar macrophages. Furthermore, morphine treatment inhibited Streptococcus pneumoniae-induced NF-B-dependent gene transcription in alveolar macrophages following 2 h of in vitro infection. S. pneumoniae infection resulted in a significant induction of NF-B activity only in TLR9 stably transfected HEK 293 cells, but not in TLR2 and TLR4 transfected HEK 293 cells, and morphine treatment inhibited S. pneumoniae-induced NF-B activity in these cells. Moreover, morphine treatment also decreased bacterial uptake and killing in alveolar macrophages. Taken together, these results suggest that morphine treatment impairs TLR9-NF-B signaling and diminishes bacterial clearance following S. pneumoniae infection in resident macrophages during the early stages of infection, leading to a compromised innate immune response.

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 Grants R01 DA12104, K02 DA015349, P50 DA11806 (to S.R.), R03 DA023353, and T32 DA07097 (to J.W.) from National Institutes of Health.

² J.W. and S.R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jinghua Wang, Department of Surgery, University of Minnesota, Mayo Mail Code 195, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: wangx219{at}umn.edu

⁴ Abbreviations used in this paper: AMs, alveolar macrophages; BAL, bronchoalveolar lavage.