Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are also involved, including matrilysin/MMP-7 – an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression.</p> <p>Results</p> <p>Here we report that MMP-7-deficient (<it>mmp7</it>^-/-) mice on the C57Bl/6 background are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG). Brain sections from MOG-primed <it>mmp7</it>^-/-mice did not show signs of immune cell infiltration of the CNS, but MOG-primed wild-type mice showed extensive vascular cuffing and mononuclear cell infiltration 15 days after vaccination. At the peak of EAE wild-type mice had MMP-7 immuno-reactive cells in vascular cuffs that also expressed the macrophage markers Iba-1 and Gr-1, as well as tomato lectin. MOG-specific proliferation of splenocytes, lymphocytes, CD4⁺and CD8⁺cells were reduced in cells isolated from MOG-primed <it>mmp7</it>^-/-mice, compared with MOG-primed wild-type mice. However, the adoptive transfer of splenocytes and lymphocytes from MOG-primed <it>mmp7</it>^-/-mice induced EAE in naïve wild-type recipients, but not naïve <it>mmp7</it>^-/-recipients. Finally, we found that recombinant MMP-7 increased permeability between endothelial cells in an <it>in vitro </it>blood-brain barrier model.</p> <p>Conclusion</p> <p>Our findings suggest that MMP-7 may facilitate immune cell access or re-stimulation in perivascular areas, which are critical events in EAE and multiple sclerosis, and provide a new therapeutic target to treat this disorder.</p

Immune stress in late pregnant rats decreases length of gestation and fecundity, and alters later cognitive and affective behaviour of surviving pre-adolescent offspring

Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long–Evans rat dams were administered lipopolysaccharide [LPS; 30 μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1 μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17–21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28–30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring