Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat

Abstract

Annexin-1, a calcium-dependent phospholipid binding protein, has been shown to act as an endogenous central neuroprotectant, notably against cerebral ischaemic damage. In the present study we extend these findings to an animal model of multiple sclerosis, EAE, and report that endogenous annexin-1 is expressed in ED1+ macrophages and resident astrocytes localized within the lesions in the central nervous system (CNS). Intracerebroventricular (i.c.v.) administration of an NH2-terminal fragment spanning amino acids 1-188 of annexin-1 after the onset of the clinical symptoms significantly reduced both the neurological severity as well as weight loss of mild EAE. Immunoneutralization of endogenous brain annexin-1 failed to exacerbate the clinical features of EAE. Thus, although the role of endogenous annexin-1 in the pathogenesis of EAE remains to be determined, our findings suggest that annexin-1 may be of therapeutic benefit to the treatment of multiple sclerosis.

Proteomic Analysis of Human Cerebral Endothelial Cells Activated by Multiple Sclerosis Serum and IFNβ-1b

“…Annexin I activates NF-kB, AP-1 and NFAT, and promotes T-cell polarization away from the Th1 phenotype. Annexin-1 has been reported in multiple sclerosis plaques (Probst-Cousin et al 2002), and has been shown to reduce disease activity in mild experimental autoimmune encephalomyelitis (Huitinga et al 1998). We found that annexin 1 abundance in brain endothelial cells was reduced by MS serum exposure, and that this decrease in annexin 1 was reversed by treatment with IFN-β.…”

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

“…Previous reports have suggested beneficial (29) and detrimental (30) roles for ANXA1 in the widely used animal model of MS, experimental autoimmune encephalitis, a confusion heightened by evidence suggesting the expression of ANXA1 in disease plaques in MS (31). Several reasons may underlie the lack of clarity over the role of ANXA1 identified by these studies, and the discrepancy with some of our findings from human disease, not least of which is the use of an animal model itself (32); however, it is important to note that we have studied the role of ANXA1 in a defined cell/tissue type and the contribution the protein makes to the maintenance of BBB integrity, rather than examining the multiple complex interacting systems that may be involved in a whole animal model of disease.…”

De novo expression of lipocortin-1 in reactive microglia and astrocytes in kainic acid lesioned rat cerebellum

“…One such molecule, which we have previously shown to be expressed by reactive astrocytes 10 days after an excitotoxic lesion to the cerebellum (Mullens et al, 1994), is lipocortin-1 (LC-1). Furthermore, LC-1 immunoreactivity has been localised to reactive astrocytes in the brains of scrapie infected mice (Williams et al, 1994(Williams et al, , 1997 and more recently Huitinga et al (1998) have shown an upregulation of this protein in macrophages (possibly activated microglial cells) and astrocytes within experimental autoimmune encephalomyelitis lesions of Lewis rat brains.…”

“…The current literature on the localisation of LC-1 is contradictory and falls essentially into two camps, one of which presents data on its location in neurons and reactive astrocytes (Johnson et al, 1989;Strijbos et al, 1991;Elderfield et al, 1993;Mullens et al, 1994;Williams et al, 1994;Buckinham, 1996;Voermans et al, 1996;Huitinga et al, 1998) the other showing that it is found only in microglia (McKanna, 1993;McKanna and Zhang, 1997). This is possibly due to problems with the specificity of the antisera and/or fixation conditions.…”