| First Author | Sun Y | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 7 | Pages | 4272-83 |
| PubMed ID | 20826748 | Mgi Jnum | J:164286 |
| Mgi Id | MGI:4831057 | Doi | 10.4049/jimmunol.1000874 |
| Citation | Sun Y, et al. (2010) TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J Immunol 185(7):4272-83 |
| abstractText | Pseudomonas aeruginosa is a major cause of blindness and visual impairment in the United States and worldwide. Using a murine model of keratitis in which abraded corneas are infected with P. aeruginosa parent and DeltafliC (aflagellar) strains 19660 and PAO1, we found that F4/80(+) macrophages were the predominant cell type in the cornea expressing TLR2, TLR4, and TLR5. Depletion of macrophages and dendritic cells using transgenic Mafia mice, in which Fas ligand is selectively activated in these cells, resulted in diminished cytokine production and cellular infiltration to the corneal stroma and unimpaired bacterial growth. TLR4(-/-) mice showed a similar phenotype postinfection with DeltafliC strains, whereas TLR4/5(-/-) mice were susceptible to corneal infection with parent strains. Bone marrow-derived macrophages stimulated with DeltafliC bacteria induced Toll/IL-1R intracellular domain (TIR)-containing adaptor inducing IFN-beta (TRIF)-dependent phosphorylation of IFN regulatory factor 3 in addition to TIR-containing adaptor protein/MyD88-dependent phosphorylation of IkappaB and nuclear translocation of the p65 subunit of NFkappaB. Furthermore, TRIF(-/-) mice showed a similar phenotype as TLR4(-/-) mice in regulating only DeltafliC bacteria, whereas MyD88(-/-) mice were unable to clear parent or DeltafliC bacteria. Finally, IL-1R1(-/-) and IL-1alpha/beta(-/-) mice were highly susceptible to infection. Taken together, these findings indicate that P. aeruginosa activates TLR4/5 on resident corneal macrophages, which signal through TRIF and TIR-containing adaptor protein/MyD88 pathways, leading to NF-kappaB translocation to the nucleus, transcription of CXCL1 and other CXC chemokines, recruitment of neutrophils to the corneal stroma, and subsequent bacterial killing and tissue damage. IL-1alpha and IL-1beta are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea. |
