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

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-κBp65. T-cell receptor δ (TCRδ)-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 γδT 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.Immunocompromised individuals are at high risk for Streptococcus pneumoniae pulmonary infection (30). Previous studies have shown that opiate abuse causes immunosuppression by disrupting both innate and adaptive components of the immune system (26, 33). Opiate abuse is a critical risk factor for increasing susceptibility and severity of bacterial infection, including S. pneumoniae (31, 32). However, additional work is needed to understand the precise mechanisms by which opiate abuse increases the susceptibility to S. pneumoniae lung infection.Interleukin-23 (IL-23) has been recently identified as a cytokine closely related to IL-12 (5). The balance between IL-23 and IL-12 controls the outcome of inflammatory responses (16). IL-23 is secreted by activated macrophages and dendritic cells (DCs) and induces memory T-cell proliferation and is the critical factor required for T-cell IL-17 expression in response to bacterial challenge (3). IL-23 release leads to the production of IL-17. Furthermore, IL-17 promotes neutrophilic inflammation by upregulating CXC chemokines and hematopoietic growth factors (13). Several recent studies report the important role of IL-23 and IL-17 in the induction of neutrophil-mediated protective immune response against extracellular bacterial or fungal pathogens, such as Klebsiella pneumoniae (14), Pseudomonas aeruginosa (12), Porphyromonas gingivalis (34), Citrobacter rodentium (20), Bacteroides fragilis (9), and Escherichia coli (27).Generally, the IL-23/IL-17 axis plays an important role in the host defense against bacterial infections (11). Previous studies have demonstrated that IL-17 is critical for the recruitment of phagocytes that leads to the clearance of S. pneumoniae colonization from the mucosal surface of the nasopharynx (18, 35). However, whether the IL-23/IL-17 axis contributes to modulating the innate immunity in response to S. pneumoniae lung infection has not been addressed. Using a well-established opiate abuse and S. pneumoniae lung infection mouse model (31, 32), we demonstrate that S. pneumoniae induces IL-23 and IL-17 expression in the lungs as early as 2 h following infection. Morphine treatment causes a decrease in both IL-23 and IL-17 synthesis during the early stages of infection, leading to delayed neutrophil recruitment. This results in an increased bacterial burden within the lungs and the initiation of systemic disease.