Leukocyte Migration And Matrix Remodeling

Leukocyte migration through basal lamina and extracellular matrix toward sites of inflammation may be related to the elevation in proteases, e.g., matrix metalloproteases (MMPs). During exacerbations of MS, elevated levels of MMP-9 and other MMPs have been reported in the CSF (MMP-9) and in MS plaques, respectively (63). Similarly, it is has been shown that one of the therapeutic mechanisms of IFN-P in MS consists of lowering the MMP-9/tissue inhibitor of MMP-1 (TIMP-1) ratio, which in turn may limit leukocyte migration (73). Neutrophil elastase degrades junctional cadherins (74), and elastase may have a similar role in neutrophil migration (45).

As mentioned previously, Biernacki et al. (66) found that lymphocyte penetration of the brain microvasculature, irrespective of Th1/Th2 polarity, caused a subsequent increase in solute leakage and cell trafficking. Sallusto et al. (62) showed that T-cell receptor stimulation of either Th1 or Th2 cells produced equivalent expression of chemokines (e.g., RANTES, MIP-1b, I-309, IL-8), which may support lymphocyte migration into the CNS. Recently, Wolf et al. (75) examined T-cell motility

Leukocyte Migration Adhesion

Fig. 1. A model for the interaction between activated leukocytes and the inflamed endothelium. This interaction includes the release of acute and chronic activators of leukocyte rolling, adhesion and emigration. Acutely, the mobilization of P-selectin and PAF as well as complement and chemoattractants (fMLP, LTB4) drive leukocyte infiltration of tissues. The adhesion and migration of leukocytes across and through tissues involves various adhesion molecules (selectins, integrins, and PECAM-1). Chronic inflammation is associated with upregulation of cytokines and chemokines and the synthesis and expression of additional adhesion molecules by endothelial cells in response to these mediators which support leukocyte homing, adhesion and emigration.

Fig. 1. A model for the interaction between activated leukocytes and the inflamed endothelium. This interaction includes the release of acute and chronic activators of leukocyte rolling, adhesion and emigration. Acutely, the mobilization of P-selectin and PAF as well as complement and chemoattractants (fMLP, LTB4) drive leukocyte infiltration of tissues. The adhesion and migration of leukocytes across and through tissues involves various adhesion molecules (selectins, integrins, and PECAM-1). Chronic inflammation is associated with upregulation of cytokines and chemokines and the synthesis and expression of additional adhesion molecules by endothelial cells in response to these mediators which support leukocyte homing, adhesion and emigration.

through fibrillar collagen and found that despite production of MMP-9, MT1-MMP, MT4-MMP, cathepsin, uPA, ADAM-9,10,11,15 and 17 by these cells, there was no dependence of guidance or motility on these enzymes (75).

5.1. Ischemic Stress and Neuroinflammation

The interruption of blood flow also triggers an inflammatory response in the postischemic cerebrum and is characterized by extensive leukocyte (especially granulocyte, monocyte) adhesion (76), infiltration, formation of cytokines and chemokines, and a form of progressive tissue injury that is leukocyte dependent. Additionally, this injury is also associated with the release of prostanoids and PAF, the induction of endothelial adhesion molecules (77) and MMPs (78), and the promotion of an exogenous (leukocyte dependent) and endogenous (endothelial, glial) (79) tissue injury and loss of blood brain barrier.

5.2. Alzheimer's Disease (AD)

AD, the most common form of dementia, affects 1% of individuals ages 65 and older. Several markers in AD are related to inflammation (e.g., apolipoprotein E, the formation of proinflammatory cytokines) (80). The brain is extensively infiltrated by leukocytes in many forms of inflammation, but in AD, neuroinflammation appears to involve activation of microglia (derived from mono-cytes), with leukocyte infiltration occurring only after microglial activation. The presence of active microglia within degenerating plaques is one of the hallmark neuropathological features of AD. The activation of these cells is induced by IFN-y and other inflammatory cytokines (81). These cells express MHC-class II molecules (HLA-DR), P-2 integrins (CD11b), leukocyte-common antigen, and the Ig receptor Fc-y RI, consistent with activation of cells in the monocyte lineage.

Highly active microglia are phagocytic and may actively remove P-amyloid, which is beneficial (82); however, active glia also release several products that may trigger inflammation, particularly reactive oxygen metabolites and NO-derived products, which account for the high degree of oxidant-stress markers in the AD plaque. McGeer et al. (80) state that complement, acute phase proteins, cytokines, chemokines, prostanoids, and proteases are all important mediators released near or by active microglia in AD. The cytokines associated with AD initiation include IL-1a, IL-1P, IL-6, TGF-P and TNF-a. In AD, some of the chemokines detected include IL-8, MCP-1, MIP-1a, MIP-1P, CXC-R2, CC-R3 and CC-R5; however, in AD, the CXCR3 receptor and its ligand fractalkine may have a dominant function in disease development. Fractalkine is produced by neurons undergoing stress, and antibody blockade of fractalkine is protective against LPS-induced stress. Hypertrophic and GFAP-expressing astrocytes are also present in the AD plaque and may help segregate the plaque from normal tissue. These activated astrocytes also express ICAM-1, making them adhesive for leukocytes. (83) T cells also appear to contribute to the inflammation seen near AD plaques. T cells have been observed in these plaques, which are CD45+ and express LFA-1, but their absolute magnitude is not very high in AD plaques.

5.3. HIV-Associated Dementia

HAD is characterized by neuroinflammation, particularly activation of macrophages and monocytes, astrogliosis, and neuronal cell injury, which produces the typical loss in cognitive impairment and delirium that are seen in in the condition. Some of the viral products secreted by HIV-infected cells, (e.g., Tat-1) seem ideally designed as inflammatory mediators. For example, we have reported that Tat-1 diminish the endothelial barrier by downregulating intercellular junctions (84), as well as upregulating E-selectin (85,86) to increase leukocyte integration within tissues, binding to tissues, and penetration of tissue barriers (e.g., the BBB). Tat-1 is now also recognized as a ligand for the Flk-1/KDR-VEGF receptor (87), which may provoke endothelial activation and proliferation-dependent CNS changes. Many other nonendothelial cells also express VEFG-R2 and respond to VEGF, including dendritic cells and monocytes/macrophages, and might be functionally altered in HIV-associated inflammation.

The pathogenesis of MS represents an ongoing neuroinflammatory response that may arise from an immune-mediated response to components in the myelin sheath and leads to leukocyte-dependent injury and loss of BBB. The "storm" of cytokines associated with exacerbations of MS creates several forms of vascular injury, including disruption of BBB (seen as gadolinium-enhancing lesions), which contribute to the development of neurological deficits by impairing normal impulse conduction. The cytokines associated with MS include a parallel upregulation of proinflammatory (IFN-y, TNF-a, TNF-P, and IL-12) and antiinflammatory cytokines (TGF-P and IL-10), as well as mobilization of IL-6 and perforin. MMPs clearly have a role in pathogenesis of MS through multiple mechanisms, including destruction of the extracellular matrix, proteolysis of endothelial junctional elements, and proteolysis of IFN-P (which is used for MS treatment). It is highly likely that the abundant Th1 cytokines in MS support the production of MMPs, particularly MMP-9, which targets the proteins described above.

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