TLR4 and TLR5 on Corneal Macrophages Regulate Pseudomonas aeruginosa Keratitis by Signaling through MyD88-Dependent and -Independent Pathways

被引:111
作者
Sun, Yan [1 ]
Karmakar, Mausita [1 ,2 ]
Roy, Sanhita [1 ]
Ramadan, Raniyah T. [1 ]
Williams, Susan R. [1 ]
Howell, Scott [1 ]
Shive, Carey L. [2 ]
Han, Yiping [3 ]
Stopford, Charles M. [4 ]
Rietsch, Arne [4 ]
Pearlman, Eric [1 ,2 ]
机构
[1] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Dept Periodont, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
TOLL-LIKE-RECEPTOR; ENDOTOXIN-INDUCED KERATITIS; CONTAINING ADAPTER PROTEIN; MARROW-DERIVED CELLS; ANTAGONIST ERITORAN; ESCHERICHIA-COLI; IMMUNE-RESPONSES; TERMINAL KINASE; OCULAR SURFACE; HOST RESPONSE;
D O I
10.4049/jimmunol.1000874
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Delta fliC (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 Delta fliC strains, whereas TLR4/5(-/-) mice were susceptible to corneal infection with parent strains. Bone marrow-derived macrophages stimulated with Delta fliC 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 I kappa B and nuclear translocation of the p65 subunit of NF kappa B. Furthermore, TRIF(-/-) mice showed a similar phenotype as TLR4(-/-) mice in regulating only Delta fliC bacteria, whereas MyD88(-/-) mice were unable to clear parent or Delta fliC bacteria. Finally, IL-1R1(-/-) and IL-1 alpha/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-kappa B 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-1 alpha and IL-1 beta are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea. The Journal of Immunology, 2010, 185: 4272-4283.
引用
收藏
页码:4272 / 4283
页数:12
相关论文
共 65 条
[1]   C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation [J].
Adhikary, Gautam ;
Sun, Yan ;
Pearlman, Eric .
JOURNAL OF LEUKOCYTE BIOLOGY, 2008, 83 (04) :991-997
[2]   The induction of macrophage gene expression by LPS predominantly utilizes Myd88-dindependent signaling cascades [J].
Björkbacka, H ;
Fitzgerald, KA ;
Huet, F ;
Li, XM ;
Gregory, JA ;
Lee, MA ;
Ordija, CM ;
Dowley, NE ;
Golenbock, DT ;
Freeman, MW .
PHYSIOLOGICAL GENOMICS, 2004, 19 (03) :319-330
[3]  
Brissette-Storkus CS, 2002, INVEST OPHTH VIS SCI, V43, P2264
[4]   Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene [J].
Burnett, SH ;
Kershen, EJ ;
Zhang, JY ;
Zeng, L ;
Straley, SC ;
Kaplan, AM ;
Cohen, DA .
JOURNAL OF LEUKOCYTE BIOLOGY, 2004, 75 (04) :612-623
[5]   Development of peritoneal adhesions in macrophage depleted mice [J].
Burnett, SH ;
Beus, BJ ;
Avdiushko, R ;
Qualls, J ;
Kaplan, AM ;
Cohen, DA .
JOURNAL OF SURGICAL RESEARCH, 2006, 131 (02) :296-301
[6]   Both TRIF- and MyD88-Dependent Signaling Contribute to Host Defense against Pulmonary Klebsiella Infection [J].
Cai, Shanshan ;
Batra, Sanjay ;
Shen, Li ;
Wakamatsu, Nobuko ;
Jeyaseelan, Samithamby .
JOURNAL OF IMMUNOLOGY, 2009, 183 (10) :6629-6638
[7]   Visualization and characterization of inflammatory cell recruitment and migration through the corneal stroma in endotoxin-induced keratitis [J].
Carlson, EC ;
Drazba, J ;
Yang, XP ;
Perez, VL .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2006, 47 (01) :241-248
[8]   The chemokine receptorCX3CR1 mediates homing of MHC class II -: Positive cells to the normal mouse corneal epithelium [J].
Chinnery, Holly R. ;
Ruitenberg, Marc J. ;
Plant, Giles W. ;
Pearlman, Eric ;
Jung, Steffen ;
McMenamin, Paul G. .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2007, 48 (04) :1568-1574
[9]   Bone Marrow Chimeras and c-fms Conditional Ablation (Mafia) Mice Reveal an Essential Role for Resident Myeloid Cells in Lipopolysaccharide/TLR4-Induced Corneal Inflammation [J].
Chinnery, Holly R. ;
Carlson, Eric C. ;
Sun, Yan ;
Lin, Michelle ;
Burnett, Sandra H. ;
Perez, Victor L. ;
McMenamin, Paul G. ;
Pearlman, Eric .
JOURNAL OF IMMUNOLOGY, 2009, 182 (05) :2738-2744
[10]   Comparison of virulence factors in Pseudomonas aeruginosa strains isolated from contact lens- and non-contact lens-related keratitis [J].
Choy, Man H. ;
Stapleton, Fiona ;
Willcox, Mark D. P. ;
Zhu, Hua .
JOURNAL OF MEDICAL MICROBIOLOGY, 2008, 57 (12) :1539-1546