IL-17 Boosts Proinflammatory Outcome of Antiviral Response in Human Cells

Abstract

Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines; however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-β–stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17–poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IκB kinases. Moreover, this synergy was blocked by an IκB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17–dependent immunopathology observed in viral infections.

Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions

“…The discovery that the TIR domain of TLRs and IL-1Rs and the SEFIR domain of IL-17Rs are part of a larger domain superfamily highlights the importance of such a motif in innate immune signalling 31 . While a previous report indicated that IL-17R signalling can co-operate in a positive manner with some TLRs 47 , we now propose that the IL-17RD-SEFIR domain negatively regulates TIR domain-containing TLRs, and the region of the IL-17RD-SEFIR domain that corresponds to box 3 of TIR domains is central to this function. It is also noteworthy that mutation of a highly conserved threonine residue in this region abolished the functional effects of the IL-17RD SEFIR domain, and it will be interesting to assess whether this residue is subject to phosphorylation and thus regulation by posttranslational modification.…”

“…Recent findings have shown that IKKi and TBK1, key kinases in activating IRFs and regulating type-I IFN expression, regulate IL-17 signalling by directly phosphorylating the adaptor molecule Act1 (refs 48,49). In addition, IL-17 is produced in response to avian influenza virus and respiratory syncytial virus and synergizes with anti-viral signalling pathways 47 . These discoveries demonstrate the growing complexity of IL-17 signalling and its impact on other signalling pathways.…”

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

“…Collectively, the lack of robust IL-17A and IL-22 production in the lungs of Cl 2 -exposed mice after microbial challenge suggests that a component of Cl 2 -induced immunosuppression is lower induction of soluble antimicrobial factors via the IL-17A and IL-22 axis. Since IL-17A and IL-22 are essential effector cytokines that coordinate the immune response to multiple lung pathogens, including A. fumigatus (26,61), influenza (33,46), Pseudomonas aeruginosa (15), Klebsiella pneumonia (4), and Staphylococcus aureus (17,32), our finding has broad implications for lung host defense mechanisms impaired by Cl 2 gas exposure (and potentially other agents that target the respiratory tract).…”

Interleukin-17 (IL-17) and IL-1 Activate Translation of Overlapping Sets of mRNAs, Including That of the Negative Regulator of Inflammation, MCPIP1

“…Marked synergy in induction of gene expression has been observed with other inflammatory stimuli, e.g. TNF (9,10) or poly(I:C) (11). The IL-17 family contains several isoforms that homo-or heterodimerize and bind to members of a distinct family of IL-17 receptors.…”