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

Abstract

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-κB-dependent gene transcription in alveolar macrophages following 2 h of in vitro infection. S. pneumoniae infection resulted in a significant induction of NF-κB 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-κB 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-κB 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.

A Serotype 3 Pneumococcal Capsular Polysaccharide-Specific Monoclonal Antibody Requires Fcγ Receptor III and Macrophages To Mediate Protection against Pneumococcal Pneumonia in Mice

“…To deplete alveolar macrophages, Wt mice were given a dose of 1 mg liposome-encapsulated clodronate intranasally as described for other studies (25,42,53) 2 days before infection. Liposomes without clodronate were used as a control.…”

Morphine Inhibits Murine Dendritic Cell IL-23 Production by Modulating Toll-like Receptor 2 and Nod2 Signaling

“…However, any compromise in the host innate immune function increases the risk of bacterial invasion resulting in pneumococcal disease (1,2). Our previous studies show that morphine impairs host innate immune response and increases susceptibility to S. pneumoniae lung infection (3,4). Furthermore, our current study show that chronic morphine disrupts the IL-23/IL-17 mediated pulmonary mucosal host defense against S. pneumoniae lung infection in an in vivo murine pulmonary S. pneumoniae infection model and in an in vitro cell infection model (5).…”

“…Dendritic cells and alveolar macrophages express various pattern recognition receptors such as Toll-like receptors (TLRs) 4 and Nod (nucleotide-binding oligomerization domain) receptors. These receptors are involved in innate immunity signaling and phagocytosis in response to microbial infections.…”

Bright Fluorescent Streptococcus pneumoniae for Live-Cell Imaging of Host-Pathogen Interactions

“…A better solution for live imaging is therefore to use strains that express fluorescence or bioluminescence. In vivo imaging with bioluminescent luciferase (lux) reporters has been used to follow the course of infection of S. pneumoniae in mice (16)(17)(18)(19). This is a powerful strategy that allows monitoring of the infection in real time using in vivo imaging systems (IVIS).…”