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Intercellular Adhesion Molecule 1 Is Important for the Development of Severe Experimental Malaria but Is Not Required for Leukocyte Adhesion in the Brain
  1. Jie Li,
  2. Wun-Ling Chang,
  3. Guang Sun,
  4. Hong-Li Chen,
  5. Robert D. Specian,
  6. Seth Mark Berney,
  7. Donald Kimpel,
  8. Neil D. Granger,
  9. Henri C. van der Heyde
  1. From the Departments of Medicine (J.L., W.-L.C., H.-L.C., S.M.B., D.K.), Microbiology and Immunology (G.S., H.C.v.d.H.), and Molecular and Cellular Physiology (R.D.S., D.N.G.); Inflammation and Immunology Research Group (S.M.B., D.K., H.C.v.d.H.); Center of Excellence in Arthritis and Rheumatism (S.M.B., D.K., H.C.v.d.H.), Louisiana State University Health Sciences Center, Shreveport, LA.
  1. This research was supported by National Institutes of Health grants K08 AI01438 (W.L.C.), POl DK43785 (D.N.G.), and ROI AI40667 (H.H.).
  2. Disclosure: Bauer PR, van der Heyde HC, Sun G, Specian RD, Granger DN. Regulation of endothelial cell adhesion molecule expression in an experimental model of cerebral malaria. Submitted for publication.
  3. Address correspondence to: Dr. Henri C. van der Heyde, Targeted Molecules Corporation, Department of Pharmacology, 3030 Bunker Hill Road, Suite 318, San Diego, CA 92109. Tel: 858-777-2818; fax: 858-777-2810; e-mail: hvande{at}targetedmolecules.com.

Abstract

Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit a systemic inflammatory response. Most investigators hypothesize that leukocytes bind to endothelial cells via intercellular adhesion molecule 1 (ICAM-1), which causes endothelial damage, increased microvascular permeability, and, ultimately, death. ICAM-1 -deficient mice on an ECM-susceptible C57BL/6 background were significantly (p = .04) protected from P. berghei mortality compared with ICAM-1 intact controls. ICAM-1 expression assessed by the dual radiolabeled monoclonal antibody technique was increased in the brain and lung in C57BL/6 mice on day 6 of P. berghei infection compared with uninfected controls (5.3-fold, p = .0003 for brain and 1.8-fold, p = .04 for lung). The increase in ICAM-1 expression coincided with significant (p < .05) increases in microvascular permeability in the brain and lung. In contrast to the hypothesized role for ICAM-1, in vivo analysis by intravital microscopy of leukocyte rolling and adhesion in brain microvasculature of mice revealed markedly increased levels of leukocyte rolling and adhesion in ICAM-1-deficient mice on day 6 of P. berghei infection compared with uninfected controls. In addition, ICAM-1 expression and microvascular permeability were increased in infected ECM-resistant BALB/c mice compared with uninfected BALB/c controls. These results collectively indicate that although ICAM-1 contributes to the mortality of experimental malaria, it is not sufficient for the development of severe experimental malaria. In addition, ICAM-1 expressed on the endothelium or on leukocytes is not required for leukocyte rolling or adhesion to the brain microvasculature of mice during P. berghei malaria. Leukocyte rolling and adhesion in the brain vasculature during P berghei malaria use different ligands than observed during inflammation in other vascular beds.

Key Words
  • brain
  • leukocytes
  • intercellular adhesion molecule 1
  • Plasmodium
  • malaria

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