title: SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling.
abstract: Pseudomonas aeruginosa keratitis destroys the cornea in susceptible Th1 responder C57BL/6 (B6), but not resistant Th2 responder (BALB/c) mice. To determine whether single Ig IL-1R-related molecule (SIGIRR) played a role in resistance, mRNA and protein expression levels were tested. Both were constitutively expressed in the cornea of the two mouse groups. A disparate mRNA and protein expression pattern was detected in the cornea of BALB/c vs B6 mice after infection. SIGIRR protein decreased significantly in BALB/c over B6 mice at 1 day postinfection. Thus, BALB/c mice were injected with an anti-SIGIRR Ab or IgG control. Anti-SIGIRR Ab over control-treated mice showed increased corneal opacity, stromal damage, and bacterial load. Corneal mRNA levels for IL-1beta, MIP-2, IL-1R1, TLR4, IL-18, and IFN-gamma and protein levels for IL-1beta and MIP-2 also were significantly up-regulated in anti-SIGIRR Ab over control mice, while no changes in polymorphonuclear cell number, IL-4, or IL-10 mRNA expression were detected. To further define the role of SIGIRR, RAW264.7 macrophage-like cells were transiently transfected with SIGIRR and stimulated with heat-killed P. aeruginosa or LPS. SIGIRR transfection significantly decreased mRNA levels for IL-1R1, TLR4, and type 1 immune response-associated cytokines (IL-12, IL-18, and IFN-gamma) as well as proinflammatory cytokines IL-1beta and MIP-2 protein expression. SIGIRR also negatively regulated IL-1 and LPS, but not poly(I:C)-mediated signaling and NF-kappaB activation. These data provide evidence that SIGIRR is critical in resistance to P. aeruginosa corneal infection by down-regulating type 1 immunity, and that it negatively regulates IL-1 and TLR4 signaling.
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA. xhuang@med.wayne.edu
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.forename: Linda D
authors.initials: LD
authors.lastname: Hazlett
authors.forename: Wenjin
authors.initials: W
authors.lastname: Du
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Barrett
mesh_terms: D000818:Animals; D002460:Cell Line; D003315:Cornea / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D007634:Keratitis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011070:Poly I-C; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D051197:Toll-Like Receptor 4; C484529:SIGIRR protein, mouse; C493487:Tlr4 protein, mouse