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. 1996 Jun 1;97(11):2485–2490. doi: 10.1172/JCI118695

Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins.

T Tang 1, P S Frenette 1, R O Hynes 1, D D Wagner 1, T N Mayadas 1
PMCID: PMC507333  PMID: 8647940

Abstract

Leukocyte accumulation in cerebrospinal fluid and disruption of the blood-brain barrier are central components of meningitis and are associated with a poor prognosis. Genetically engineered deficiencies or functional inhibition of endothelial leukocyte adhesion receptors P-, or P- plus E-selectins, lead to deficits in leukocyte rolling and extravasation. However, their impact on meningeal inflammation has not been tested previously. An acute cytokine-induced meningitis model associated with significant cerebrospinal fluid leukocyte accumulation (averaging 14,000 leukocytes/microl as early as 4 h) and blood-brain barrier permeability was developed in adult mice. This model was applied to mice deficient in P-selectin and mice doubly deficient in P- and E-selectins. Partial inhibition of cerebrospinal fluid leukocyte influx and permeability was noted in P-selectin-deficient mice. Mice doubly deficient in P- and E-selectins displayed a near complete inhibition of these parameters. Our results suggest that P- and E-selectins cooperatively contribute to meningitis and that functional blocking of both endothelial selectins in conjunction with antibiotics may provide a therapeutic approach for treatment of bacterial meningitis.

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Selected References

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  1. Barkalow F. J., Goodman M. J., Mayadas T. N. Cultured murine cerebral microvascular endothelial cells contain von Willebrand factor-positive Weibel-Palade bodies and support rapid cytokine-induced neutrophil adhesion. Microcirculation. 1996 Mar;3(1):19–28. doi: 10.3109/10739689609146779. [DOI] [PubMed] [Google Scholar]
  2. Carlos T. M., Harlan J. M. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed] [Google Scholar]
  3. Cooper D., Butcher C. M., Berndt M. C., Vadas M. A. P-selectin interacts with a beta 2-integrin to enhance phagocytosis. J Immunol. 1994 Oct 1;153(7):3199–3209. [PubMed] [Google Scholar]
  4. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  5. Frei K., Siepl C., Groscurth P., Bodmer S., Schwerdel C., Fontana A. Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells. Eur J Immunol. 1987 Sep;17(9):1271–1278. doi: 10.1002/eji.1830170909. [DOI] [PubMed] [Google Scholar]
  6. Frenette P. S., Mayadas T. N., Rayburn H., Hynes R. O., Wagner D. D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996 Feb 23;84(4):563–574. doi: 10.1016/s0092-8674(00)81032-6. [DOI] [PubMed] [Google Scholar]
  7. Gotsch U., Jäger U., Dominis M., Vestweber D. Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-alpha in vivo. Cell Adhes Commun. 1994 Apr;2(1):7–14. doi: 10.3109/15419069409014198. [DOI] [PubMed] [Google Scholar]
  8. Granert C., Raud J., Xie X., Lindquist L., Lindbom L. Inhibition of leukocyte rolling with polysaccharide fucoidin prevents pleocytosis in experimental meningitis in the rabbit. J Clin Invest. 1994 Mar;93(3):929–936. doi: 10.1172/JCI117098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Griffin D. E. Immunoglobulins in the cerebrospinal fluid: changes during acute viral encephalitis in mice. J Immunol. 1981 Jan;126(1):27–31. [PubMed] [Google Scholar]
  10. Kurose I., Yamada T., Wolf R., Granger D. N. P-selectin-dependent leukocyte recruitment and intestinal mucosal injury induced by lactoferrin. J Leukoc Biol. 1994 Jun;55(6):771–777. doi: 10.1002/jlb.55.6.771. [DOI] [PubMed] [Google Scholar]
  11. Labow M. A., Norton C. R., Rumberger J. M., Lombard-Gillooly K. M., Shuster D. J., Hubbard J., Bertko R., Knaack P. A., Terry R. W., Harbison M. L. Characterization of E-selectin-deficient mice: demonstration of overlapping function of the endothelial selectins. Immunity. 1994 Nov;1(8):709–720. doi: 10.1016/1074-7613(94)90041-8. [DOI] [PubMed] [Google Scholar]
  12. Leist T. P., Frei K., Kam-Hansen S., Zinkernagel R. M., Fontana A. Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, meningitis. Evaluation in murine model infections and in patients. J Exp Med. 1988 May 1;167(5):1743–1748. doi: 10.1084/jem.167.5.1743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lo S. K., Lee S., Ramos R. A., Lobb R., Rosa M., Chi-Rosso G., Wright S. D. Endothelial-leukocyte adhesion molecule 1 stimulates the adhesive activity of leukocyte integrin CR3 (CD11b/CD18, Mac-1, alpha m beta 2) on human neutrophils. J Exp Med. 1991 Jun 1;173(6):1493–1500. doi: 10.1084/jem.173.6.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mayadas T. N., Johnson R. C., Rayburn H., Hynes R. O., Wagner D. D. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell. 1993 Aug 13;74(3):541–554. doi: 10.1016/0092-8674(93)80055-j. [DOI] [PubMed] [Google Scholar]
  15. McCracken G. H., Jr, Mustafa M. M., Ramilo O., Olsen K. D., Risser R. C. Cerebrospinal fluid interleukin 1-beta and tumor necrosis factor concentrations and outcome from neonatal gram-negative enteric bacillary meningitis. Pediatr Infect Dis J. 1989 Mar;8(3):155–159. [PubMed] [Google Scholar]
  16. Mulligan M. S., Paulson J. C., De Frees S., Zheng Z. L., Lowe J. B., Ward P. A. Protective effects of oligosaccharides in P-selectin-dependent lung injury. Nature. 1993 Jul 8;364(6433):149–151. doi: 10.1038/364149a0. [DOI] [PubMed] [Google Scholar]
  17. Mustafa M. M., Lebel M. H., Ramilo O., Olsen K. D., Reisch J. S., Beutler B., McCracken G. H., Jr Correlation of interleukin-1 beta and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J Pediatr. 1989 Aug;115(2):208–213. doi: 10.1016/s0022-3476(89)80067-8. [DOI] [PubMed] [Google Scholar]
  18. Mustafa M. M., Ramilo O., Olsen K. D., Franklin P. S., Hansen E. J., Beutler B., McCracken G. H., Jr Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis. J Clin Invest. 1989 Oct;84(4):1253–1259. doi: 10.1172/JCI114292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Quagliarello V. J., Scheld W. M. New perspectives on bacterial meningitis. Clin Infect Dis. 1993 Oct;17(4):603–610. doi: 10.1093/clinids/17.4.603. [DOI] [PubMed] [Google Scholar]
  20. Quagliarello V. J., Wispelwey B., Long W. J., Jr, Scheld W. M. Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. J Clin Invest. 1991 Apr;87(4):1360–1366. doi: 10.1172/JCI115140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ramilo O., Sáez-Llorens X., Mertsola J., Jafari H., Olsen K. D., Hansen E. J., Yoshinaga M., Ohkawara S., Nariuchi H., McCracken G. H., Jr Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation. J Exp Med. 1990 Aug 1;172(2):497–507. doi: 10.1084/jem.172.2.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Robbins D. S., Shirazi Y., Drysdale B. E., Lieberman A., Shin H. S., Shin M. L. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol. 1987 Oct 15;139(8):2593–2597. [PubMed] [Google Scholar]
  23. Rodewald A. K., Onderdonk A. B., Warren H. B., Kasper D. L. Neonatal mouse model of group B streptococcal infection. J Infect Dis. 1992 Sep;166(3):635–639. doi: 10.1093/infdis/166.3.635. [DOI] [PubMed] [Google Scholar]
  24. Sharar S. R., Sasaki S. S., Flaherty L. C., Paulson J. C., Harlan J. M., Winn R. K. P-selectin blockade does not impair leukocyte host defense against bacterial peritonitis and soft tissue infection in rabbits. J Immunol. 1993 Nov 1;151(9):4982–4988. [PubMed] [Google Scholar]
  25. Sharar S. R., Winn R. K., Murry C. E., Harlan J. M., Rice C. L. A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery. 1991 Aug;110(2):213–220. [PubMed] [Google Scholar]
  26. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  27. Sáez-Llorens X., Jafari H. S., Severien C., Parras F., Olsen K. D., Hansen E. J., Singer I. I., McCracken G. H., Jr Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis. J Clin Invest. 1991 Dec;88(6):2003–2011. doi: 10.1172/JCI115527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tan T. Q., Smith C. W., Hawkins E. P., Mason E. O., Jr, Kaplan S. L. Hematogenous bacterial meningitis in an intercellular adhesion molecule-1-deficient infant mouse model. J Infect Dis. 1995 Feb;171(2):342–349. doi: 10.1093/infdis/171.2.342. [DOI] [PubMed] [Google Scholar]
  29. Tsai Y. H., Williams E. B., Hirth R. S., Price K. E. Pneumococcal meningitis-therapeutic studies in mice. Chemotherapy. 1975;21(6):342–357. doi: 10.1159/000221879. [DOI] [PubMed] [Google Scholar]
  30. Tuomanen E. I., Saukkonen K., Sande S., Cioffe C., Wright S. D. Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med. 1989 Sep 1;170(3):959–969. doi: 10.1084/jem.170.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tuomanen E. Adjunctive therapy of experimental meningitis: agents other than steroids. Antibiot Chemother (1971) 1992;45:184–191. doi: 10.1159/000421008. [DOI] [PubMed] [Google Scholar]
  32. Tuomanen E., Baruch A. New antibodies as adjunctive therapies for Gram-positive bacterial meningitis. Pediatr Infect Dis J. 1989 Dec;8(12):923–928. doi: 10.1097/00006454-198912000-00047. [DOI] [PubMed] [Google Scholar]
  33. Tuomanen E. Modulation of inflammation in bacterial meningitis. Isr J Med Sci. 1994 May-Jun;30(5-6):339–341. [PubMed] [Google Scholar]
  34. Waage A., Halstensen A., Shalaby R., Brandtzaeg P., Kierulf P., Espevik T. Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J Exp Med. 1989 Dec 1;170(6):1859–1867. doi: 10.1084/jem.170.6.1859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weller A., Isenmann S., Vestweber D. Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem. 1992 Jul 25;267(21):15176–15183. [PubMed] [Google Scholar]
  36. Yam L. T., Li C. Y., Crosby W. H. Cytochemical identification of monocytes and granulocytes. Am J Clin Pathol. 1971 Mar;55(3):283–290. doi: 10.1093/ajcp/55.3.283. [DOI] [PubMed] [Google Scholar]

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