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Title: Bacterial Pathogens Activate a Common Inflammatory Pathway through IFNλ Regulation of PDCD4}
Article:
Abstract:
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.
Introduction:
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[1]–[3]. Activation of type I IFN signaling can be either protective or detrimental to the host depending on the specific pathogen[4]–[9]. 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[1],[10]–[16]. Interferons induce expression of downstream genes through distinct receptors. Type I IFN signals through the ubiquitously expressed interferon-α/β receptor( IFNAR), while the type III IFN( IFNλ) family, composed of IL-28A/B and IL-29, signals through the more cell specific receptor complex of IL-10R2 and IL-28R[17]–[21]. Following activation of either IFN pathway, an autocrine signaling network mediates the cellular response, primarily through JAK/STAT signaling and the induction of IFN dependent gene expression. It would seem that the two IFNs activate redundant downstream signaling pathways. However altered signaling kinetics and the limited distribution of IL-28R, restricted primarily to mucosal tissues, suggest distinct roles for type I and type III IFN depending on the infection site[22]–[28]. For example in the lung type III IFN is the primary IFN produced by respiratory epithelial cells in response to viral stimulation and is required for clearance of influenza from the airway[29]–[32]. Several of the immunological effects of IFNλ such as upregulation of MHC I and II, induction of NF-κB dependent cytokine production and effects on DC maturation and differentiation, could be highly relevant to the pathogenesis of bacterial infection[33]–[36]. Interferon signaling is linked to the regulation of micro RNAs, small non-coding RNA inhibitors of mRNA translation capable of directly influencing innate immune signaling[4]–[9]. In tumor cells, miR-21 targets the tumor suppressor programmed cell death protein 4( PDCD4) promoting tumor growth and contributing to the inflammatory tumor microenvironment[1],[10]–[16]. PDCD4 represses translation of cellular mRNA through its binding to eukaryotic initiation factor 4A( eIF4A)[17]–[21]. Phosphorylation of PDCD4 by the ribosomal S6 kinase( p70S6K) results in release of eIF4A from PDCD4, ubiquitin dependent degredation of PDCD4, and enhanced mRNA translation[22]–[28]. Inflammatory cytokine production in response to toll like receptor( TLR) 2 or 4 activation by decorin or lipopolysaccharide( LPS) is significantly influenced by expression of miR-21 and PDCD4[29]–[32]. Therefore the pro-inflammatory contribution of PDCD4 to host signaling during bacterial pneumonia could significantly contribute to lung pathology[33]–[36]. In the experiments detailed in this report, we examined the importance of type III IFNs in the innate immune response to two major airway pathogens, USA300 MRSA and P. aeruginosa, currently the most common causes of ventilator associated pneumonia[37],[38]. We found that IFNλ is induced in the course of bacterial airway infection and results in downregulation of the microRNA miR-21, sustained expression of PDCD4, and increased proinflammatory cytokine production. Mice lacking the IFNλ receptor, IL-28R, or PDCD4 had significantly improved clearance of both airway pathogens and less pulmonary pathology associated with reduced levels of inflammatory cytokines.
Discussion:
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[23]–[28],[30],[47],[48]. 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[49],[50]. 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[51]. 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[21],[28]. In contrast to the beneficial effects of IFNλ in the eradication of viral pathogens, our data suggest that IFNλ promotes a prolonged inflammatory cytokine response to bacterial pathogens that detracts from the efficiency of bacterial clearance and promotes pathology. Mice lacking the type III IFN receptor demonstrated significantly improved clearance of S. aureus and P. aeruginosa coincident with a reduced duration of the host inflammatory response. Particularly in the pathogenesis of pneumonia, the balance between pro and anti-inflammatory signaling is critical. While the mechanism through which the inflammatory milieu affects bacterial clearance is unclear, our data clearly demonstrate that reducing levels of inflammatory cytokines through modulation of IFNλ or inhibition of IL-1R improves clearance of S. aureus and P. aeruginosa[11]. Once a sufficient number of phagocytes are recruited to the airways to deal with the pathogens, excessive cytokine production, particularly toxic cytokines such as IL-1β, elicits tissue damage and impairs normal host defenses. A major effector of IFNλ signaling is PDCD4, which appears to be regulated by multiple pathways in response to infection. A confirmed target of miR-21, PDCD4 influences production of pro-inflammatory signaling through its interaction with AP-1, NF-κB, and eIF4A, and has been linked to the inflammatory microenvironment surrounding tumor cells[10],[12],[29],[31],[33],[52]. Similar to previous findings with LPS, S. aureus SpA, through its interaction with TNFR1 upregulates PDCD4 in epithelial cells, promoting pro-inflammatory signaling while inhibiting anti-inflammatory cytokine production. It is likely that additional S. aureus pathogen associated molecular patterns( PAMPs) such as the lipoproteins that activate TLR2 also participate. Following ligation of IL-28R by IFNλ, STAT3 suppresses expression of miR-21 resulting in increased expression of PDCD4. MiRNAs like miR-21 comprise a regulatory system which makes subtle changes to mRNA expression levels, including the genes involved in Toll-like receptor signaling, and therefore are capable of having significant affects on innate immunity[7]–[9],[31],[53]. MiR-21, specifically, is induced by NF-κB signaling and has been implicated in the regulation of TLR2 mediated signaling in both skin and lung inflammation[33],[54]–[57]. We similarly observe rapid increases in miR-21 during the initial 4 hour infection with either S. aureus or P. aeruginosa, and sustained expression of miR-21 in IL-28R−/− mice was associated with reduced levels of inflammatory cytokines in the airway. As predicted by our in vitro studies, in mice expressing IL-28R reduced levels of miR-21 at 18 hours post infection correlated with prolonged PDCD4 mRNA expression. Mice lacking PDCD4 were better able to clear USA300 from their lungs, similar to previous findings demonstrating PDCD4 null mice are resistant to lethal LPS challenge[31]. Therefore mice lacking IL-28R are less susceptible to S. aureus and P. aeruginosa induced lung damage due in part to reduced PDCD4 and a shortened inflammatory response. A second pathway acting through mTOR and p70S6K regulates PDCD4 function by phosphorylating PDCD4, inhibiting its interaction with AP-1 and eIF4A and promoting its degradation[17],[19],[22],[29]. Our data suggest that type III IFN has an inhibitory affect on p70S6K and PDCD4 phosphorylation. In vitro IFNλ treatment of epithelial cells reduced p70S6K phosphorylation. In vivo, PDCD4 was strongly phosphorylated in uninfected IL-28R−/− mice while phosphorylation was not observed in uninfected control mice. Rapid turnover of PDCD4 due to phosphorylation dependent degradation, or an inability of PDCD4 to bind eIF4A in IL-18R null mice could further limit its affects on signaling. Increases in p70S6K phosphorylation during bacterial infection were IL-28R independent and were only observed 18 hours following infection with P. aeruginosa. The ability to activate different regulatory pathways such as p70S6K signaling could contribute to the differences in cytokine induction observed during S. aureus and P. aeruginosa infections. For example levels of TNF and IL-10 were significantly different between WT and IL-28R−/− mice during PAK not USA300 infections, whereas IL-1β was significantly different during a S. aureus infection. Thus IFNλ and PDCD4 are conserved elements in the response to airway pathogens which clearly have other differential effects in inducing innate immunity. The selective expression of IL-28R, substantially more abundant on murine and human epithelial cells than on immune cells as previously shown and demonstrated by the inability of macrophages to respond to IFNλ( Fig. S4), may also be important in the specific cytokine responses evoked by the different pathogens[28]. Epithelial cells are not the primary producers of IL-1β in response to PAK, therefore IL-1β levels in the airways of P. aeruginosa infected WT and IL-28R−/− mice were not different[11],[58]. It is unclear which cells in the lung produce IL-1β in response to S. aureus. Our data suggest that IL-1β producing cells express IL-28R, as cytokine levels were significant reduced in IL-28R null mice. While we do not propose that IL-1β is the sole cytokine responsible for lung damage in response to S. aureus, inhibition of this signaling pathway in WT mice does improve clearance of S. aureus and limits the extent of tissue damage. We conclude that while the specific cytokines modulated by type III IFN are different in the context of specific bacterial infections, the overall affect of inhibiting IL-28R dependent signaling is a reduction of lung inflammation and improved bacterial clearance. The type III IFN pathway is recognized as an important host defense pathway for the eradication of viral infection and tumor growth and the distribution of the receptor at mucosal sites makes it an active participant in the innate immune response to bacterial pathogens as well. While differences in the expression of PAMPs and their receptors, mechanisms of p70S6K and PDCD4 phosphorylation, and ultimately levels of cytokine expression are evident in the models of S. aureus and P. aeruginosa pneumonia, IFNλ functions as a central regulator of airway inflammation in both types of bacterial pneumonia. Given the pathology associated with excess cytokine induction in the airways, targeting specific components of the type III IFN/PDCD4 regulatory pathway could be a potential therapy for limiting lung damage in the setting of acute airway infection.
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 .