Induction of inflammation
Cells of the intracerebral microvasculature and the CP epithelium are, among many other cells of the CNS, capable of expressing several cytokines and other proinflammatory molecules . In humans, the classic proinflammatory cytokines such as TNF-a, IL-1|3, and IL-6, as well as a great variety of other cytokines, are present in CSF during meningitis. In addition, CXC and CC chemokines have been found in the CSF of these patients [13, 165]. Concentrations of IL-1|3, but not IL-6 and TNF-a, are associated with significantly worse disease outcome or disease severity .
Numerous observations highlight that the cerebral endothelium is capable of releasing an array of factors for leukocyte attraction. In experimental studies it was shown that HBMEC are capable of secreting IL-8 in response to challenge with S. agalactiae . After infection of HBMEC with N. menin-gitidis, the endothelial cells were also shown to respond with IL-8 production with the p38 mitogen-activated (MAP) kinase being centrally involved .
S. suis infection of HBMEC led to the production of IL-8 and MCP-1 by the endothelial cells in a time- and dose-dependent manner .
The presence of binding sites for MCP-1 and MIP-1a on human brain microvessels  suggests that chemokines produced locally by perivascu-lar astrocytes and microglia either diffuse or are transported to the endothe-lial cell surface, where they are immobilized for presentation to leukocytes , a process that has been demonstrated in peripheral endothelium with the chemokine IL-8 .
Following stimulation with LPS, TNF-a, IFN-y, and IL-1p alone or in combination, HBMEC released significant amounts of RANTES and MIP-1P .
Various studies have demonstrated that BMECs are well capable of producing and secreting proinflammatory cytokines including IL-1a and p, IL-6, and GM-CSF [167, 170, 171].
In a BBB in vitro model, infection of HBMEC with N. meningitidis resulted in the release of IL-6 by the endothelial cells . Using the same BBB model, challenge of HBMEC with S. suis led, apart from secretion of chemokines, to the production of IL-6 as well .
An established example of brain microvascular endothelial activation during an infectious disease is the cerebral manifestation of malaria. IL-1p and TNF-a are predominant cytokines released during the disease by the cerebral endothelium .
It has been known for some time that several subpopulations of resident macrophages are associated with the CNS. However, defining their role in microbial infection is difficult, as the number of morphological and functional studies is limited and few types of cells in neuroimmunology have prompted so much controversy as have the members of the monocyte lineage in the CNS . In the pathogenesis of bacterial meningitis, these macrophages could act as sentinels at the interface between CNS and the circulation.
Perivascular macrophages are a minor population in the CNS situated adjacent to endothelial cells immediately beyond the basement membrane of medium to small vessels . They constitute a subpopulation of resident macrophages in the CNS that by virtue of their strategic location at the BBB potentially form a first line of defense against invading bacteria, and may play a role in the regulation of the inflammatory response during bacterial meningitis .
Recent studies on the putative function of these cells have used a rat model of pneumococcal meningitis with depletion of meningeal and peri-vascular macrophages by intraventricular injection of mannosylated clo-dronate liposomes . This depletion aggravated clinical symptoms and resulted in higher bacterial titers both in the blood and the CSF. In addition, a decreased CSF pleocytosis despite elevated relevant chemokines (e.g., MIP-2), cytokines (e.g., IL-6) and a higher expression of vascular adhesion molecules (e.g.,VCAM-1) was observed .
Subpopulations of resident macrophages associated with the ventricular space comprise a family of specific histiocytes that constitute the epiplexus ("Kolmer") cells and supraependymal cells apart from free-floating phagocytes . Immunohistochemical studies on rat brains have revealed extensive populations predominantly on the ventricular side of the CP .
Very few functional observations have been made so far. LPS injected intraperitoneally in infant rats led to a vigorous up-regulation of complement receptor 3, leukocyte common antigens and major histocompatibility complex (MHC) classes I and II, suggesting an immunoregulatory role . Upon injection of LPS and following in situ hybridization of rat brains, IL-1a and IL-1p as well as IL-1 receptor antagonist mRNA expression were noted primarily within the CPs and the CVOs. Interestingly, characterization of the cell types expressing IL-1 mRNA identified the cells as belonging to the monocyte/macrophage lineage .
In this respect, it is of note that recent observations confirmed the CPs to contain extensive populations of dendritic cells in rat and in humans , in the latter even bearing the potential of acting as a reservoir or port of entry for HIV-1 infection .
In a study using environmental scanning and confocal electron microscopy MHC class II-positive cells were found in abundance in the CPs of rat brains. The dendriform morphology and large size of these epiplexus/mac-rophage-like cells led to the assumption that these cells could indeed represent "real" dendritic cells ideally situated to sample CSF-borne antigens functioning as sentinels at the blood-CSF barrier .
The CNS orchestrates an organized innate immune response during systemic bacterial/viral infection. This inflammatory response, characterized by the expression of Toll-like receptors (TLRs), cytokines, chemokines and proteins of the complement system, is predominantly elicited in the CVOs and the CPs, i.e., structures that are devoid of the BBB and in close contact with the circulation environment. The inflammatory stimulus extends progressively into microglia across the brain parenchyma and may lead to an adaptive immune response . Distinct TLRs have been proposed as key molecules in the selective recognition of main pathogen associated molecular patterns (PAMPs) that are released by either gram-negative (LPS) or gram-positive bacteria (peptidoglycan) .
In recent studies, murine challenge with LPS demonstrated a constitutive expression of both TLR4 and CD14, in structures that can be reached by the bloodstream: the CVOs, the CPs and the leptomeninges. These data provided the anatomical evidence that an exogenous ligand (LPS) has an endogenous receptor (CD14) in the brain in regions that can be reached by the systemic circulation. It has been proposed that this might allow intracel-lular signaling and then rapid transcription of pro-inflammatory cytokines, first within these organs and thereafter throughout the brain parenchyma in response to cell wall components of gram-negative bacteria . In addition, this response could have been modulated by activation of TLR2 by peptidoglycan of gram-positive bacteria .
Challenge of human embryonic cell lines selectively overexpressing TLRs with live S. pneumoniae, Hib, and N. meningitidis showed that the bacteria use distinct sets of TLR2, -4 and -9 to trigger inflammatory responses. Heat-inactivated pneumococci or meningococci did not elicit comparable responses . This is in line with observations in a murine model of experimental meningitis where TLR2 participated in sensing and activating the initial immune response to intracisternal challenge with S. pneumoniae. Nonetheless, other TLRs such as TLR4 were believed to be additionally involved . Other observations on the interaction of BMEC and N. men-ingitidis point to TLR-independent mechanisms .
Besides confining entry of blood-borne pathogens into the CNS by means of tightly sealed cell-to-cell interfaces, HBMECs display distinct antimicrobial properties . Experiments from our laboratory demonstrated that bacteria such as Staphylococcus aureus as well as intracellular parasites such as Toxoplasma gondii were restricted in their growth in HBMECs after stimulation with interferon-y [94, 192]. Activation of indoleamine 2,3-dioxygenase (IDO) with subsequent degradation of the essential amino acid L-tryptophan has been found to be the principle antimicrobial mechanism. The in vivo relevance of this mechanism is emphasized by studies on patients suffering from bacterial meningitis . For example, in children with purulent meningitis, concentrations of kynurenine, the primary meta bolic product of tryptophan degradation, were more than 40 times higher than in healthy controls .
We have recently shown that IDO activation also accounts for growth restriction of S. suis in experiments with primary porcine CP epithelial cells after activation with proinflammatory cytokines . The CP as a source of tryptophan degradation has been shown in an early study on the rabbit brain, where highest IDO activity could be demonstrated in the CP .
Teleologically, inducible tryptophan depletion by the brain endothelium would be particularly advantageous at the strategically important interface between blood and brain parenchyma. In the light of related antimicrobial action and IDO expression in neighboring cells in the CNS such as astrocytes, microglia and neurons , the cerebral microvasculature or the CPs could act in concert with them by collectively reducing tryptophan influx into the brain tissue, restricting the amount of tryptophan freely available to the pathogen. The blood-CNS interfaces thus not only seem to play a role as barriers against microbial penetration, but also once invasion has occurred.
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