Inhibition of Macrophage Migration Inhibitory Factor Ameliorates Ocular -Induced Keratitis
Pseudomonas aeruginosa causes severe sight-threatening corneal infections, with the inflammatory response to the pathogen being the major factor resulting in damage to the cornea that leads to loss of visual acuity. We found that mice deficient for macrophage migration inhibitory factor (MIF), a key regulator of inflammation, had significantly reduced consequences from acute P. aeruginosa keratitis. This improvement in the outcome was manifested as improved bacterial clearance, decreased neutrophil infiltration, and decreased inflammatory responses when P. aeruginosa-infected MIF knock out (KO) mice were compared to infected wild-type mice. Recombinant MIF applied to infected corneas restored the susceptibility of MIF deficient mice to P. aeruginosa-induced disease, demonstrating that MIF is necessary and sufficient to cause significant pathology at this immune privileged site. A MIF inhibitor administered during P. aeruginosa-induced infection ameliorated the disease-associated pathology. MIF regulated epithelial cell responses to infection by enhancing synthesis of proinflammatory mediators in response to P. aeruginosa infection and by promoting bacterial invasion of corneal epithelial cells, a correlate of virulence in the keratitis model. Our results uncover a host factor that elevates inflammation and propagates bacterial cellular invasion, and further suggest that inhibition of MIF during infection may have a beneficial therapeutic effect.
Vyšlo v časopise:
Inhibition of Macrophage Migration Inhibitory Factor Ameliorates Ocular -Induced Keratitis. PLoS Pathog 6(3): e32767. doi:10.1371/journal.ppat.1000826
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000826
Souhrn
Pseudomonas aeruginosa causes severe sight-threatening corneal infections, with the inflammatory response to the pathogen being the major factor resulting in damage to the cornea that leads to loss of visual acuity. We found that mice deficient for macrophage migration inhibitory factor (MIF), a key regulator of inflammation, had significantly reduced consequences from acute P. aeruginosa keratitis. This improvement in the outcome was manifested as improved bacterial clearance, decreased neutrophil infiltration, and decreased inflammatory responses when P. aeruginosa-infected MIF knock out (KO) mice were compared to infected wild-type mice. Recombinant MIF applied to infected corneas restored the susceptibility of MIF deficient mice to P. aeruginosa-induced disease, demonstrating that MIF is necessary and sufficient to cause significant pathology at this immune privileged site. A MIF inhibitor administered during P. aeruginosa-induced infection ameliorated the disease-associated pathology. MIF regulated epithelial cell responses to infection by enhancing synthesis of proinflammatory mediators in response to P. aeruginosa infection and by promoting bacterial invasion of corneal epithelial cells, a correlate of virulence in the keratitis model. Our results uncover a host factor that elevates inflammation and propagates bacterial cellular invasion, and further suggest that inhibition of MIF during infection may have a beneficial therapeutic effect.
Zdroje
1. RobertsonDM
PetrollWM
JesterJV
CavanaghHD
2007 The role of contact lens type, oxygen transmission, and care-related solutions in mediating epithelial homeostasis and pseudomonas binding to corneal cells: an overview. Eye Contact Lens 33 394 398; discussion 399–400
2. RobertsonDM
PetrollWM
JesterJV
CavanaghHD
2007 Current concepts: contact lens related Pseudomonas keratitis. Cont Lens Anterior Eye 30 94 107
3. FleiszigSM
EvansDJ
2002 The pathogenesis of bacterial keratitis: studies with Pseudomonas aeruginosa. Clin Exp Optom 85 271 278
4. FleiszigSM
2006 The Glenn A. Fry award lecture 2005. The pathogenesis of contact lens-related keratitis. Optom Vis Sci 83 866 873
5. O'BrienTP
MaguireMG
FinkNE
AlfonsoE
McDonnellP
1995 Efficacy of ofloxacin vs cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group. Arch Ophthalmol 113 1257 1265
6. CalandraT
RogerT
2003 Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3 791 800
7. FlasterH
BernhagenJ
CalandraT
BucalaR
2007 The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol Endocrinol 21 1267 1280
8. CalandraT
BernhagenJ
MetzCN
SpiegelLA
BacherM
1995 MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377 68 71
9. BernhagenJ
CalandraT
CeramiA
BucalaR
1994 Macrophage migration inhibitory factor is a neuroendocrine mediator of endotoxaemia. Trends Microbiol 2 198 201
10. CalandraT
BucalaR
1995 Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock. J Inflamm 47 39 51
11. BozzaM
SatoskarAR
LinG
LuB
HumblesAA
1999 Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 189 341 346
12. Assuncao-MirandaI
AmaralFA
BozzaFA
FagundesCT
SousaLP
2009 Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection. FASEB J
13. SevketogluE
YilmazA
GedikbasiA
KaryagarS
KiyakA
2009 Urinary macrophage migration inhibitory factor in children with urinary tract infection. Pediatr Nephrol
14. HouXQ
GaoYW
YangST
WangCY
MaZY
2009 Role of macrophage migration inhibitory factor in influenza H5N1 virus pneumonia. Acta Virol 53 225 231
15. MatsudaA
TagawaY
YoshidaK
MatsudaH
NishihiraJ
1997 Expression of macrophage migration inhibitory factor in rat retina and its immunohistochemical localization. J Neuroimmunol 77 85 90
16. MatsudaA
TagawaY
MatsudaH
NishihiraJ
1997 Expression of macrophage migration inhibitory factor in corneal wound healing in rats. Invest Ophthalmol Vis Sci 38 1555 1562
17. MatsudaA
TagawaY
MatsudaH
NishihiraJ
1996 Identification and immunohistochemical localization of macrophage migration inhibitory factor in human cornea. FEBS Lett 385 225 228
18. ApteRS
SinhaD
MayhewE
WistowGJ
NiederkornJY
1998 Cutting edge: role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege. J Immunol 160 5693 5696
19. HazlettLD
2005 Inflammatory response to Pseudomonas aeruginosa keratitis. Ocul Surf 3 S139 141
20. ZhangJ
WuXY
YuFS
2005 Inflammatory responses of corneal epithelial cells to Pseudomonas aeruginosa infection. Curr Eye Res 30 527 534
21. ZhuH
ConibearTC
ThuruthyilSJ
WillcoxMD
2008 Pseudomonas aeruginosa quorum-sensing signal molecules induce IL-8 production by human corneal epithelial cells. Eye Contact Lens 34 179 181
22. MiyazakiD
InoueY
Araki-SasakiK
ShimomuraY
TanoY
1998 Neutrophil chemotaxis induced by corneal epithelial cells after herpes simplex virus type 1 infection. Curr Eye Res 17 687 693
23. WinnerM
MeierJ
ZierowS
RendonBE
CrichlowGV
2008 A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res 68 7253 7257
24. LiaoH
BucalaR
MitchellRA
2003 Adhesion-dependent signaling by macrophage migration inhibitory factor (MIF). J Biol Chem 278 76 81
25. LueH
ThieleM
FranzJ
DahlE
SpeckgensS
2007 Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26 5046 5059
26. HazlettLD
2002 Pathogenic mechanisms of P. aeruginosa keratitis: a review of the role of T cells, Langerhans cells, PMN, and cytokines. DNA Cell Biol 21 383 390
27. ThakurA
XueM
StapletonF
LloydAR
WakefieldD
2002 Balance of pro- and anti-inflammatory cytokines correlates with outcome of acute experimental Pseudomonas aeruginosa keratitis. Infect Immun 70 2187 2197
28. XueML
ThakurA
WillcoxMD
ZhuH
LloydAR
2003 Role and regulation of CXC-chemokines in acute experimental keratitis. Exp Eye Res 76 221 231
29. PrestonMJ
FleiszigSM
ZaidiTS
GoldbergJB
ShortridgeVD
1995 Rapid and sensitive method for evaluating Pseudomonas aeruginosa virulence factors during corneal infections in mice. Infect Immun 63 3497 3501
30. GadjevaM
WangY
HorwitzBH
2007 NF-kappaB p50 and p65 subunits control intestinal homeostasis. Eur J Immunol 37 2509 2517
31. ZaidiTS
LyczakJ
PrestonM
PierGB
1999 Cystic fibrosis transmembrane conductance regulator-mediated corneal epithelial cell ingestion of Pseudomonas aeruginosa is a key component in the pathogenesis of experimental murine keratitis. Infect Immun 67 1481 1492
32. FichorovaRN
Richardson-HarmanN
AlfanoM
BelecL
CarbonneilC
2008 Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: a multicenter study. Anal Chem 80 4741 4751
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 3
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Binds and Protects a Nuclear Noncoding RNA from Cellular RNA Decay Pathways
- Endocytosis of the Anthrax Toxin Is Mediated by Clathrin, Actin and Unconventional Adaptors
- Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8 T Cells
- Inhibition of Macrophage Migration Inhibitory Factor Ameliorates Ocular -Induced Keratitis