Date Published: October 3, 2013
Publisher: Public Library of Science
Author(s): Taylor S. Cohen, Alice S. Prince, Ambrose Cheung.
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.
The interferon (IFN) family is composed of three subgroups (types I, II, and III IFN), and through their distinct receptors, IFNs signal through STAT transcription factors to upregulate expression of over 300 IFN dependent genes. In the lung bacterial pathogen associated molecular patterns (PAMPs) can be internalized and thus gain access to the intracellular receptors involved in type I IFN signaling –. Activation of type I IFN signaling can be either protective or detrimental to the host depending on the specific pathogen –. Type I IFNs promote the pathogenesis of Staphylococcus aureus pulmonary infection through upregulation of CXCR3 chemokines and T-cell recruitment while improving eradication of Pseudomonas aeruginosa by reducing inflammasome signaling , –.
Much like the other members of the IFN family, IFNλ is required for host defense against viral pathogens and is capable of inhibiting tumor growth –, , , . There is clearly a major role for IFNλ in the successful clearance of the hepatitis C virus consistent with expression of IL-28R on hepatocytes , . Type III IFN has also been linked to killing of the intracellular bacterial pathogen Listeria monocytogenes, correlating with reduced colonization of the spleen and liver . Fitting with the abundance of IL-28R in the respiratory tract, we found a major role for IFNλ signaling in the pathogenesis of both S. aureus and P. aeruginosa pneumonia , .