Experimental Cerebral Malaria Develops Independently of Endothelial Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Ramos, Theresa N.; Bullard, Daniel C.; Darley, Meghan M.; McDonald, Kristin; Crawford, David F.; Barnum, Scott R.

doi:10.1074/jbc.c113.457028

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…More strikingly, the density of ICAM-1 positive leukocytes in postcapillary venules was significantly higher (t-test: T (8) = 4.30, P <0.01) during ECM compared to hyperparasitemia ( Figure 5G ). Thus, ECM is associated with the arrest of large numbers of ICAM-1+ leukocytes, consistent with a recent report on the contribution of leukocyte ICAM-1 to ECM development [66] .…”

Section: Resultssupporting

confidence: 92%

Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

et al. 2014

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Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8+ T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45hi CD8+ T cells, ICAM-1+ macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8+ T cells and ICAM+ macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.

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Section: Resultssupporting

confidence: 92%

Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

et al. 2014

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“…Activated effector T cells have been accounted to play a decisive role in the disruption of the BBB and disease progression [ 41 ]. Parasite-specific cell-mediated responses increase systemic and local inflammation, leading to an activation of endothelial cells; genetically deficient mice or depletion strategies had impressively demonstrated the importance of adhesion molecules such the intercellular adhesion molecule 1 (ICAM-1), P-selectin on activated endothelial cells and leukocytes [ 42 , 43 ] in the induction of ECM. In addition, local effector processes such as intravascular accumulation of leukocytes and CD8 + T cells [ 44 ] and the production of granzyme B [ 26 ] and perforin [ 45 , 46 ] during ECM are well described.…”

Section: Discussionmentioning

confidence: 99%

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators

et al. 2018

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Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4–6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.

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“…In studies simultaneously comparing the course of ECM in different lines of ICAM-1 mutant mice, it has now been shown that the ECM phenotype varies directly with the combination of isoforms expressed (53). Not surprisingly, Icam1 tm1Alb mice were highly resistant to ECM with over 90% of mice surviving ten days post-infection, a time at which all wild type mice had succumbed to disease (Table 1).…”

Section: Does Differential Icam-1 Isoform Expression Alter Disease Phmentioning

confidence: 99%

ICAM-1: Isoforms and Phenotypes

Ramos

Bullard

Barnum

2014

The Journal of Immunology

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128

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Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, immunological synapse formation and, numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane bound and soluble ICAM-1 isoforms which arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types is poorly understood. In the generation of ICAM-1-deficient mice, two isoform-deficient ICAM-1 mutants were inadvertently produced due to alternative splicing. These mice along with true ICAM-1-deficient mice and newly generated ICAM-1 transgenic mice have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis.

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Experimental Cerebral Malaria Develops Independently of Endothelial Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Cited by 14 publications

References 43 publications

Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators

ICAM-1: Isoforms and Phenotypes

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