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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 Laboratórium

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PLOS Pathogens


2010 Číslo 3
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Autori: MUDr. Tomáš Ürge, PhD.

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