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

TIR8, also known as SIGIRR (single Ig IL-1-related receptor), is an orphan receptor member of IL-1 receptor/Toll-like (IL-1R/TLR) receptor super family. Recent evidence suggests that it is an inhibitor of IL-1R/TLR signalling, acting as a decoy for key components of the cascade. TIR8 activity seems to be specific for IL-1/TLR members, as it exerts its negative regulatory function on IL-1, IL-18 and several TLR ligand-dependent NF-kB activation. Its negative regulatory function is mediated through the direct effect on signal-induced NF-kB and JNK activation. 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. In response to P. aeruginosa infection, NF-kB is rapidly translocated to the nuclei of airway epithelial cells and several studies have demonstrate the critical role of myeloid differentiation factor 88 (MyD88) as mediators of NF-kB translocation, but neither TLR2, TLR4, nor TLR5 was individually required for this early response, whereas it have been proved that the IL-1 receptor (IL-1R), which transduces its response via MyD88, plays an important role in the response to P. aeruginosa in respiratory epithelial cells. In order to examined the role of TIR8/SIGIRR during lung infection with P. aeruginosa, we compare the percent survival, bacterial outgrowth and local production of cytokines and chemokines in Tir8 -/- and wild-type mice during respiratory tract infection with this pathogen.