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The Blood Brain Barrier: a Critical Interface in Neuroinflammation and Route to Therapeutic Intervention

Trevor Owens1*, Jessica L. Teeling1 and V. H. Perry1
  • 1 University of Southern Denmark, Medical Biotechnology Center, Denmark

The COST Action BM0603 Inflammation in Brain Disease/Neurinfnet was set up to promote interchange of ideas between those who study neuroinflammatory disease (such as multiple sclerosis, MS), and neurodegenerative disease (such as Alzheimer's Disease, AD). Axonal loss is a recently-appreciated feature of MS and activation of possibly pro-inflammatory glial cells feature in AD. Thus, inflammation and degeneration are represented in both diseases, despite the fact that MS and AD are used as paradigms for the respective pathological processes. It was felt that both interest groups could learn from each other and that training a new generation of scientists with ‘crossover skills’ would enable further advances in understanding brain disease.

It is readily accepted that the blood-brain barrier (BBB) plays a pivotal role in MS. Cells of the adaptive immune system must enter the central nervous system (CNS) in order to exert their effect. Immune cell entry to the CNS involves interaction with specialized components of the BBB, notably the perivascular space of post-capillary venules, and is driven by chemokines that are produced at, and act at, the BBB (1). Acquisition of antigens from the CNS by antigen-presenting cells (APC) within these perivascular spaces is considered to play an important role in providing stimulus for myelin-specific T cell entry to the CNS (2, 3). How these APC's acquire antigen from within the CNS parenchyma has not been very well understood.

It has been proposed that ß-amyloid, which contributes to the characteristic plaques around degenerating nerves in both AD and in old age, is drained from the CNS via perivascular routes along cerebral blood vessels, and that this drainage is a normal clearance mechanism that prevents buildup in the CNS (4). Understanding these mechanisms would be very important for prevention and treatment of AD.

Recent evidence from both pre-clinical and clinical studies suggests that systemic inflammation in animals or patients with a chronic neurodegenerative disease is associated with an acceleration of disease progression (5, 6). Systemic infections also may trigger clinical relapses in MS patients (7). The routes by which systemic inflammation communicates with the brain include both neural and humoral signaling but a key feature is signaling at and across the intact BBB (8). In healthy individuals this signaling across the BBB provokes both metabolic and behavioural changes, part of our normal homeostatic mechanisms that protect us during infection. Signaling of systemic inflammatory events across the BBB thus offers a potentially important target for modulation of disease progression in those with ongoing neuroinflammatory and neurodegenerative disease.

BBB function may therefore contribute to neuroinflammation via dysregulated entry of antigenspecific T cells, to neurodegeneration via compromised removal of toxic products of neuronal damage and death, and to disease progression via signaling of systemic inflammation or infection. Members of Neurinfnet focus on aspects of BBB function and dysfunction, specifically whether the BBB may serve as a target for therapy to prevent immune infiltration, to promote clearance of betaamyloid and other potential toxins from the CNS, and to modulate signals from systemic inflammation and infection. The challenge is to enable beneficial roles of the BBB without triggering pathological outcomes.

Projects within Neurinfnet, that will be presented here, study the relative roles of vascular endothelium and glia limitans in regulation of solute and cellular traffic between the CNS and blood circulation, the role of perivascular drainage in clearance of potentially toxic ß-amyloid from the CNS and the signaling of systemic inflammation across the BBB.
Solute access to the perivascular space from blood circulation can be tracked using tracer molecules such as the enzyme horseradish peroxidase (HRP) or dyes. Historically it was observed that although occasional phagocytic cells in the perivascular space at selected sites were seen to have taken up tracer dye, tracers generally do not cross the un-inflamed vascular endothelium, consistent with tight inter-endothelial cell junctions. Such observations of a solute barrier were the original basis for the term 'blood-brain barrier' (9). To investigate this further we studied access of HRP and leukocytes to the CNS in transgenic mice that overexpress the chemokine CCL2 under control of an MBP promoter. Both HRP and leukocytes accumulated in white matter perivascular spaces ((10), Füchtbauer et al, unpublished). In this situation, the glia limitans restricts passage of both solute tracers and immune cells to the parenchyma. Leukocyte infiltration and tracer leakage to the parenchyma could be induced by systemic treatment of these mice with pertussis toxin. Such leukocyte traffic across the glia limitans is dependent on matrix metalloproteinase (MMP) action (10). By contrast, in response to axonal injury and synaptic degeneration in the hippocampus dentate gyrus, leukocytes are driven to enter the parenchyma in response to glial-derived CCL2 (11), but HRP leakage cannot be demonstrated ((12), Füchtbauer et al, unpublished). Upregulation of the angiotensin II receptor AT2 at the glia limitans correlated with solute rather than leukocyte entry (Füchtbauer et al, unpublished). Thus the barrier can be selective, depending perhaps on regional influences, or on the nature or level of stimulus, or all three.

The perivascular space around the cerebral arterioles and arteries, as noted above, is proposed to play a critical role in solute drainage from the brain (4). To test this hypothesis we set out to develop a model of immune complex formation in the brain that might inhibit the natural drainage of CNS soluble proteins from the brain. Using an Arthus-like reaction we have shown that immune complexes formed in or adjacent to the perivascular space will indeed alter the drainage pathway of a tracer from the brain parenchyma along this route (Carare et al unpublished). Preliminary results suggest that IgG influx is increased under inflammatory conditions (Teeling and de Vries, unpublished), and this IgG accumulation induces FcR-dependent microglial/macrophage activation and increased expression of MHC molecules (Teeling et al unpublished). We hypothesize that increased influx of antigen-specific IgG into the brain, as for example seen in MS or paraneoplastic disorders, may change the CNS microenvironment resulting in a further compromised BBB, increased cytokine production and MHC expression, allowing increased antigen presentation to infiltrating T cells. Blockade or modulation of FcR may be exploited as novel therapeutic strategies.

In an animal model of chronic neurodegeneration, murine prion disease, the innate immune response in the brain is characterized by the presence of large numbers of microglia with an activated morphology but an anti-inflammatory phenotype. In these animals a systemic inflammatory challenge with lipopolysaccharide (LPS), to mimic aspects of a systemic infection, leads to a switch in the microglia phenotype from an anti-inflammatory to a pro-inflammatory phenotype with an exacerbation of acute symptoms, acute neuronal loss and accelerated disease progression (see (5) for refs). The molecular signaling pathways across the BBB from circulating inflammatory molecules may involve circulating cytokines in some (8) but not all circumstances (13). Our recent studies suggest that there are multiple routes by which circulating mediators impact on particular behaviours, and induce cytokine synthesis within the brain parenchyma (14).

Thus there is a growing body of evidence that functions of the BBB play a critical role in the regulation of diverse aspects of neuroinflammation. Understanding signaling processes at the BBB offers potential for therapeutic intervention to modulate neuroinflammatory processes while preserving essential features of BBB function,

References

1. Owens, T., I. Bechmann, and B. Engelhardt. 2008. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113-1121.

2. Bailey, S. L., B. Schreiner, E. J. McMahon, and S. D. Miller. 2007. CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 8:172-180.

3. Greter, M., F. L. Heppner, M. P. Lemos, B. M. Odermatt, N. Goebels, T. Laufer, R. J. Noelle, and B. Becher. 2005. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328-334.

4. Carare, R. O., M. Bernardes-Silva, T. A. Newman, A. M. Page, J. A. Nicoll, V. H. Perry, and R. O. Weller. 2008. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131-144.

5. Cunningham, C., S. Campion, K. Lunnon, C. L. Murray, J. F. Woods, R. M. Deacon, J. N. Rawlins, and V. H. Perry. 2009. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 65:304-312.

6. Holmes, C., C. Cunningham, E. Zotova, J. Woolford, C. Dean, S. Kerr, D. Culliford, and V. H. Perry. 2009. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768-774.

7. Buljevac, D., H. Z. Flach, W. C. Hop, D. Hijdra, J. D. Laman, H. F. Savelkoul, F. G. van Der Meche, P. A. van Doorn, and R. Q. Hintzen. 2002. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 125:952-960.

8. Dantzer, R., J. C. O'Connor, G. G. Freund, R. W. Johnson, and K. W. Kelley. 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46-56.

9. Bechmann, I., I. Galea, and V. H. Perry. 2007. What is the blood-brain barrier (not)? Trends Immunol 28:5-11.

10. Toft-Hansen, H., R. Buist, X. J. Sun, A. Schellenberg, J. Peeling, and T. Owens. 2006. Metalloproteinases Control Brain Inflammation Induced by Pertussis Toxin in Mice Overexpressing the Chemokine CCL2 in the Central Nervous System. J Immunol 177:7242-7249.

11. Babcock, A. A., W. A. Kuziel, S. Rivest, and T. Owens. 2003. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23:7922-7930.

12. Jensen, M. B., B. Finsen, and J. Zimmer. 1997. Morphological and immunophenotypic microglial changes in the denervated fascia dentata of adult rats: correlation with blood-brain barrier damage and astroglial reactions. Exp Neurol 143:103-116.

13. Teeling, J. L., L. M. Felton, R. M. Deacon, C. Cunningham, J. N. Rawlins, and V. H. Perry. 2007. Subpyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines. Brain Behav Immun 21:836-850.

14. Teeling, J. L., C. Cunningham, T. A. Newman, and V. H. Perry. 2009. The effect of non-steroidal antiinflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1. Brain Behav Immun.

Conference: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.

Presentation Type: Oral Presentation

Topic: Presentations

Citation: Owens T, Teeling JL and Perry VH (2010). The Blood Brain Barrier: a Critical Interface in Neuroinflammation and Route to Therapeutic Intervention. Front. Pharmacol. Conference Abstract: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU. doi: 10.3389/conf.fphar.2010.02.00016

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Received: 10 Mar 2010; Published Online: 10 Mar 2010.

* Correspondence: Trevor Owens, University of Southern Denmark, Medical Biotechnology Center, Winsloewparken, Denmark, towens@health.sdu.dk