Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis

Treschow

The Journal of Immunology

et al. 2003

190

Since the basic mechanisms behind the beneficial effects of IFN-β in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-β gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-β knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-γ in response to recall Ag. Consequently, we addressed the effect of IFN-β on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-β KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN-β is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-α production in IFN-β KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-β KO mice, as measured by IFN-γ and IL-4 production. We suggest that lack of endogenous IFN-β in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.

Section: Discussionmentioning

confidence: 99%

IFN-β Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis

Treschow

The Journal of Immunology

et al. 2003

190

“…They are transcriptionally regulated by various factors, such as proinflammatory cytokines, growth factors or hormones, while their activity in tissues is regulated by tissue inhibitors of metalloproteinases (TIMPs). MMPs disrupt basal lamina of BBB and contribute to parenchymal damage in neuroinflammation [37]. Infiltration of immune cells through parenchymal basal lamina requires activity of MMP2 and MMP9, which cleave distroglycan receptors leading to destabilization of astrocyte end-feet anchorage to parenchymal membrane.…”

Section: Masons and Wreckersmentioning

confidence: 99%

Astrocytes in the tempest of multiple sclerosis

2011

Astrocytes are the most abundant cell population within the CNS of mammals. Their glial role is perfectly performed in the healthy CNS as they support functions of neurons. The omnipresence of astrocytes throughout the white and grey matter and their intimate relation with blood vessels of the CNS, as well as numerous immunity‐related actions that these cells are capable of, imply that astrocytes should have a prominent role in neuroinflammatory disorders, such as multiple sclerosis (MS). The role of astrocytes in MS is rather ambiguous, as they have the capacity to both stimulate and restrain neuroinflammation and tissue destruction. In this paper we present some of the proved and the proposed functions of astrocytes in neuroinflammation and discuss the effect of MS therapeutics on astrocytes.

“…MMPs are highly regulated in their expression, secretion and activity [29]. Generally, they are expressed at low or undetectable levels; however, expression is rapidly induced at times of active tissue remodeling.…”

Section: Introductionmentioning

confidence: 99%

“…Upregulation of MMPs has been reported in multiple sclerosis, stroke, HIV-dementia, bacterial meningitis, Alzheimer's disease and brain tumors [43,46,47,63]. Animal models used to study distinct CNS disorders have concentrated on the use of MMP inhibitors or MMP deficient animals to evaluate the lack of MMPs in the progression of the disorder [7,24,28,29,35,43]. Studies in humans have focused on detection of MMPs in serum, CSF or post-mortem specimens, and in general the data obtained correlates positively with the severity of the disorder [5,14,22,26,33,48].…”

Section: Introductionmentioning

confidence: 99%

Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers

Alvarez

Teale

2008

Brain Research

During the course of murine neurocysticercosis (NCC), disruption of the unique protective barriers in the central nervous system (CNS) is evidenced by extravasation of leukocytes. This process varies according to the anatomical sites and diverse vascular beds analyzed. To examine mechanisms involved in the observed differences, the expression and activity of eight matrix metalloproteinases (MMPs) were analyzed in a murine model of NCC. The mRNA expression of the MMPs studied was upregulated as a result of infection, and active MMPs were mainly detected in leukocytes migrating into the brain. Polarized expression and gelatinolytic activity of several MMPs were identified in immune cells extravasating pial vessels as early as 1 day post infection. In contrast, leukocytes expressing active MMPs and extravasating parenchymal vessels were not observed until 5 weeks post infection. In ventricular areas, most of the MMP activity was detected in leukocytes traversing the ependyma from leptomeningeal infiltrates. In addition, immune cells continued to express active MMPs after exiting vessels suggesting that enzymatic activity of MMPs is not just required for diapedesis. These results correlate with our previous studies showing differential kinetics in the disruption of the CNS barriers upon infection and help document the important role of MMPs during leukocyte infiltration and inflammation.