Bacterial pathogens activate a common inflammatory pathway through IFNλ regulation of PDCD4

The type III interferon (IFNλ) receptor IL-28R is abundantly expressed in the respiratory tract and has been shown essential for host defense against some viral pathogens, however no data are available concerning its role in the innate immune response to bacterial pathogens. Staphylococcus aureus and Pseudomonas aeruginosa induced significant production of IFNλ in the lung, and clearance of these bacteria from the lung was significantly increased in IL-28R null mice compared to controls. Improved bacterial clearance correlated with reduced lung pathology and a reduced ratio of pro- vs anti-inflammatory cytokines in the airway. In human epithelial cells IFNλ inhibited miR-21 via STAT3 resulting in upregulation of PDCD4, a protein known to promote inflammatory signaling. In vivo 18 hours following infection with either pathogen, miR-21 was significantly reduced and PDCD4 increased in the lungs of wild type compared to IL-28R null mice. Infection of PDCD4 null mice with USA300 resulted in improved clearance, reduced pathology, and reduced inflammatory cytokine production. These data suggest that during bacterial pneumonia IFNλ promotes inflammation by inhibiting miR-21 regulation of PDCD4.
Author Summary The role of interferons (types I, II, and III) in viral and bacterial infections has been a topic of intense research over the last decade. The contribution of the type I interferons during bacterial pneumonias particularly has been shown to be highly variable depending on the specific pathogen. Our data for the first time demonstrate that type III interferon plays a significant role in the pathogenesis of bacterial pneumonia, and its contribution is similar in both Gram positive and Gram negative infections. We show in epithelial cells that miR-21 and PDCD4 are downstream effectors of type III interferon that prolong production of inflammatory cytokines. Utilizing mice that lack the receptor for type III interferon or PDCD4, we show that inhibiting this pathway improves bacterial clearance from the airways and lung tissue. These data suggest novel targets for therapy in a variety of bacterial pneumonias.