Morphine Disrupts Interleukin-23 (IL-23)/IL-17-Mediated Pulmonary Mucosal Host Defense against Streptococcus pneumoniae Infection

Abstract

Streptococcus pneumoniae is a pathogen that causes serious respiratory disease and meningitis in the immunocompromised drug abuse population. However, the precise mechanisms by which drug abuse compromises the host immune defense to pulmonary S. pneumoniae infection is not fully understood. Using a well-established murine model of opiate abuse and S. pneumoniae lung infection, we explored the influence of morphine treatment on the interleukin-23 (IL-23)/IL-17 axis and related innate immunity. Impairment of early IL-23/IL-17 production caused by morphine treatment was associated with delayed neutrophil migration and decreased pneumococcal clearance. Furthermore, morphine treatment impaired MyD88-dependent IL-23 production in alveolar macrophages and dendritic cells in response to in vitro S. pneumoniae cell infection. Moreover, morphine treatment significantly inhibited the S. pneumoniae-induced phosphorylation of interferon response factor 3 (IRF3), ATF2, and NF-Bp65. T-cell receptor ␦ (TCR␦)-deficient mice showed a decrease in IL-17 production and a severely weakened capacity to clear lung S. pneumoniae infection. Finally, morphine treatment resulted in diminished secretion of antimicrobial proteins S100A9 and S100A8/A9 during early stages of S. pneumoniae infection. In conclusion, morphine treatment causes a dysfunction in IL-23-producing dendritic cells and macrophages and IL-17-producing ␥␦T lymphocytes in response to S. pneumoniae lung infection. This leads to diminished release of antimicrobial S100A8/A9 proteins, compromised neutrophil recruitment, and more-severe infection.

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

“…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). However, the cellular and molecular mechanisms by which morphine modulates S. pneumoniae induced IL-23 production remain to be elucidated.…”

“…1 infection model and in vitro cell infection model. Although our previous works have established that IRF3, ATF2, and NF-B were selectively inactivated in morphine-treated and S. pneumoniae-infected DCs, the mechanism for this repression has never been defined (5). In this study, DCs were treated with morphine and then infected with S. pneumoniae.…”

“…Morphine treatment disrupts the IL-23/IL-17 axis, which leads to a diminished host release of antimicrobial proteins S100A8/A9. This results in decreased neutrophil recruitment and more severe infection (5). However, the cellular and molecular mechanisms by which morphine treatment leads to compromised IL-23 production in response to S. pneumoniae has not been delineated.…”

“…The inhibitory peptide contains a sequence from the MyD88 TIR homodimerization domain, which specifically inhibits the MyD88-dependent pathway (5).…”

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

“…Chronic opiate administration is known to be immunosuppressive clinically and specifically inhibits T-cell, B-cell, and natural killer-cell function. 11,44,45 Moreover, DALDA has been shown to be protective in two T-cell driven models of murine colitis: the TNBS and adoptive transfer of CD45RB hi CD4 ϩ T-cell models. 19 This implies that MOR-mediated immunosuppression may provide a potential mechanism for MORmediated protection from intestinal injury.…”