Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells

Abstract

We have investigated the effects of Chlamydia pneumoniae on human brain endothelial cells (HBMECs) and human monocytes as a mechanism for breaching the blood-brain barrier (BBB) in Alzheimer's disease (AD). HBMECs and peripheral blood monocytes may be key components in controlling the entry of C. pneumoniae into the human brain. Our results indicate that C. pneumoniae infects blood vessels and monocytes in AD brain tissues compared with normal brain tissue. C. pneumoniae infection stimulates transendothelial entry of monocytes through HBMECs. This entry is facilitated by the up-regulation of VCAM-1 and ICAM-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes. C. pneumoniae infection in HBMECs and THP-1 monocytes up-regulates monocyte transmigration threefold in an in vitro brain endothelial monolayer. In this way, C. pneumoniae infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS resulting from infection at the level of the vasculature. Thus, infection at the level of the vasculature may be a key initiating factor in the pathogenesis of neurodegenerative diseases such as sporadic AD.

Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10

“…C. pneumoniae has been reported to stimulate transendothelial entry of monocytes through human brain endothelial cells 23 and all three Chlamydiaceae species multiply in monocytes. The findings of Wilke et al 28 of an increased number of monocytes in the blood of schizophrenic persons also support our assumptions.…”

“…22 The importance of simultaneous infections with two C. species will be discussed later, particularly with regard to the blood-brain barrier. 23 Association of infections and HLA-A10 Elaboration of cytokines and specific neurotrophins during an immune response is controlled by the HLA system. We found recently an increased susceptibility to schizophrenia associated with HLA-A10 genotypes in two independent groups of patients.…”

Immunopathological aspects of age-related macular degeneration

“…Indeed, chronic inflammation from C. pneumoniae might be the trigger that activates the alternative complement pathway and ultimately leads to complement overactivity in patients with the Y402H risk variant of CFH, which as we have discussed above leads to impaired complement inhibitory function by CFH. Macrophage accumulation has also been associated with AMD, and prior studies have shown that C. pneumoniae infection promotes differentiation of monocytes to macrophages, as well as migration of monocytes to target tissues [93,94]. In fact, monocytes infected by C. pneumoniae upregulate various adhesion molecules and exhibit enhanced migration through the blood-brain barrier [94].…”

“…Macrophage accumulation has also been associated with AMD, and prior studies have shown that C. pneumoniae infection promotes differentiation of monocytes to macrophages, as well as migration of monocytes to target tissues [93,94]. In fact, monocytes infected by C. pneumoniae upregulate various adhesion molecules and exhibit enhanced migration through the blood-brain barrier [94]. This raises the question of whether Chlamydia can similarly enhance monocyte entry through the blood retinal barrier, as well as subsequent macrophage accumulation associated with AMD.…”

Anti-VCAM-1 Antibodies did not Protect against Ischemic Damage Either in Rats Or in Mice

“…Vascular cell adhesion molecule-1 supports the adhesion of the primary leukocyte populations present in atherosclerotic plaques and may contribute to the quantitative predominance of monocytes over lymphocytes (Gerszten et al, 1998). Vascular cell adhesion molecule-1 facilitates transendothelial entry of circulating monocytes through human brain endothelial cells (MacIntyre et al, 2003), and it plays an important role in leukocyte recruitment in brain diseases, as shown in experimental models of systemic lupus erythematosus (James et al, 2003), and in chronic graft-versus-host disease (Sostak et al, 2004). At the bedside, soluble VCAM-1 concentration in plasma is raised in patients with acute stroke (Blann et al, 1999), and a two-fold increase of this parameter was found independently associated to poor outcome after stroke (Chamorro et al, 2002).…”