The inflammasome is a multimolecular complex that assembles in response to danger signals from pathogens or other harmful agents for the production of the inflammatory cytokines IL-1β and IL-18, which recruit neutrophils and monocytes to the site of infection or injury. The inflammasome consists of a pattern recognition receptor and the protease caspase-1, with the adapter molecule ASC serving to link the two. Upon signaling from a pathogen- or danger-associated molecular pattern, the pattern recognition receptor protein undergoes a conformational change and oligomerizes, causing subsequent binding and oligomerization of ASC, which in turn binds to and dimerizes the caspase-1 progenitor molecule, procasepase-1. Dimers of procaspase-1 then self-cleave to produce the enzymatically active form caspase-1, which goes on to cleave the progenitors of IL-1β and IL-18 into their active forms for release from the cell.
Inflammation is necessary for the clearance of pathogens, but too much inflammation causes damage to healthy tissue. Such injury can exacerbate the severity of infectious disease. Hence, a delicate balance must be maintained to ensure the optimal host response to pathogens. The pattern recognition receptors NLRP3 and NLRC4 are NOD-like receptors that form inflammasomes in response to infection by influenza A virus (IAV) and Pseudomonas aeruginosa, respectively. We have found that the activation of these particular inflammasomes is regulated by the type 3 intermediate filament protein vimentin. Compared with wild-type mice, vimentin-null mice infected with lethal doses IAV or P. aeruginosa show decreased production of IL-1β and IL-18, reduced lung inflammation and injury, and in the case of IAV infection, improved survival. We hypothesize that vimentin acts as a scaffold for the assembly of the NLRP3 and NLRC4 inflammasomes, and that its absence greatly reduces the efficiency of the activation process. Thus less IL-1β and IL-18 is produced, resulting in decreased inflammation and a corresponding reduction in disease severity.
Infection with IAV also results in the activation of the NOD-like receptor NOD2, which phosphorylates the transcription factor IRF3, which then translocates to the nucleus to induce activation of interferon genes. NOD2 has been shown to regulate the RIG-1 signaling pathway, which leads to activation of NF-kB, which is also crucial for inflammatory cytokine induction and IRF3 activation. NOD2 has been shown to interact with vimentin, suggesting that vimentin regulates the NOD2 signaling cascade as well as the NLRP3 inflammasome during IAV infection. Hence, vimentin would be involved in both the antiviral response and the inflammatory response to IAV. We continue to investigate the role of vimentin in NOD2 signaling, as well as other intersections between the antiviral and inflammatory pathways. Altogether, our findings contribute to greater understanding of the process of, and possible ways to counter, the damaging inflammation that can accompany severe infectious disease in the lung.