Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

Abstract

Toll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulator in vivo under different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused by Pseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acute P. aeruginosa infection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-␥], tumor necrosis factor alpha [TNF-␣], IL-1␤, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense against P. aeruginosa acute lung infection can be improved by blocking IL-1 since exaggerated IL-1␤ production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8 ؊/؊ IL-1RI ؊/؊ double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused by P. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.

Bone morphogenetic protein 4 inhibits liposaccharide‐induced inflammation in the airway

“…A possible reason for these opposite function of BMP4 in regulating immune responses under different conditions may be due to the cross-talk between BMP family members and other signaling pathways [15], among them the TLR signaling that mediates innate or adaptive immune responses might be a top candidate [16][17][18][19][20]. The different pathophysiological environment might also contribute to the differential effects of BMP4 in cells from different location.…”

The Toll Interleukin-1 Receptor (IL-1R) 8/Single Ig Domain IL-1R-Related Molecule Modulates the Renal Response to Bacterial Infection

“…In a murine model of pulmonary tuberculosis and acute Pseudomonas aeruginosa lung infection, TIR8 Ϫ/Ϫ mice were shown to have increased mortality (13,37). Huang et al (16) reported that mice treated with anti-TIR8 Ab had increased stromal damage and bacterial load in the cornea in a model of Pseudomonas aeruginosa keratitis.…”

Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia

“…After priming by LPS or other PAMPs, activation of the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome by internalized flagellin stimulates caspase-1, resulting in pyroptosis -a highly proinflammatory mode of cell death associated with tissue damage -and release of inflammatory cytokines, such as IL-1β and IL-18 (14)(15)(16)(17)(18)(19)(20)(21)(22). Both IL-1β and IL-18 have been identified as mediators of local inflammation in the lung and tissue remodeling systemically (1, 2, [23][24][25][26][27][28][29].…”