Role of TIR8/SIGIRR, a negative regulator of IL-1/TLR signaling, in the pulmonary immune response to pseudomonas aeruginosa infection

TIR8/SIGIRR is a member of the IL-1 receptor/Toll-like receptor (TLR/IL-1R) superfamily, expressed by epithelial cells and immature dendritic cells, which negatively regulates the TLR/IL-1R signaling pathway leading to NF-kB activation and inflammatory responses. NF-kB, by regulating the transcription of genes for numerous inflammatory factors including IL-6 and CXCL1, is a central mediator of the lung epithelial cell response to the infection by Pseudomonas aeruginosa, a Gram-negative pathogen that can cause serious lung infection in immunocompromised individuals and cystic fibrosis patients. On the other side, uncontrolled cytokine release leads to pathological response that inhibit bacterial clearance. To study the role of TIR8/SIGIRR in the pathogenesis of P. aeruginosa-induced lung immunopathology in vivo, Tir8-deficient mice and wild-type mice were intratracheally inoculated with laboratory strain PAO1 Seattle. The absence of TIR8/SIGIRR had a deleterious effect on the host in terms of mortality and clearance of P. aeruginosa from the lung in an acute model of infection, as reflected by an increased number of colony-forming units (cfu) (P < 0.05, Tir8 -/- mice vs. Tir8+/+ mice). Increased susceptibility to P. aeruginosa was also associated to an exacerbated local production of proinflammatory cytokines (IL-1β, TNFα, IL-6 and IL-23) and chemokines (KC, MIP-2, JE, IFNγ, MIP-1α, RANTES and EOTAXIN) in lungs and serum. These results suggest that TIR8/SIGIRR, by negatively regulating NF-kB activity, plays a key role in modulating lung inflammation due to P. aeruginosa which, if uncontrolled, is responsible of inhibition of bacterial clearance and exacerbation of tissue pathology.