Abstract
Theiler’s murine encephalomyelitis (TME) represents a versatile animal model for studying the pathogenesis of demyelinating diseases such as multiple sclerosis. Hallmarks of TME are demyelination, astrogliosis, as well as inflammation. Previous studies showed that matrix metalloproteinase 12 knockout (Mmp12−/−) mice display an ameliorated clinical course associated with reduced demyelination. The present study aims to elucidate the impact of MMP12 deficiency in TME with special emphasis on astrogliosis, macrophages infiltrating the central nervous system (CNS), and the phenotype of microglia/macrophages (M1 or M2). SJL wild-type and Mmp12−/− mice were infected with TME virus (TMEV) or vehicle (mock) and euthanized at 28 and 98 days post infection (dpi). Immunohistochemistry or immunofluorescence of cervical and thoracic spinal cord for detecting glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), chemokine receptor 2 (CCR2), CD107b, CD16/32, and arginase I was performed and quantitatively evaluated. Statistical analyses included the Kruskal–Wallis test followed by Mann–Whitney U post hoc tests. TMEV-infected Mmp12−/− mice showed transiently reduced astrogliosis in association with a strong trend (p = 0.051) for a reduced density of activated/reactive microglia/macrophages compared with wild-type mice at 28 dpi. As astrocytes are an important source of cytokine production, including proinflammatory cytokines triggering or activating phagocytes, the origin of intralesional microglia/macrophages as well as their phenotype were determined. Only few phagocytes in wild-type and Mmp12−/− mice expressed CCR2, indicating that the majority of phagocytes are represented by microglia. In parallel to the reduced density of activated/reactive microglia at 98 dpi, TMEV-infected Mmp12−/− showed a trend (p = 0.073) for a reduced density of M1 (CD16/32- and CD107b-positive) microglia, while no difference regarding the density of M2 (arginase I- and CD107b-positive) cells was observed. However, a dominance of M1 cells was detected in the spinal cord of TMEV-infected mice at all time points. Reduced astrogliosis in Mmp12−/− mice was associated with a reduced density of activated/reactive microglia and a trend for a reduced density of M1 cells. This indicates that MMP12 plays an important role in microglia activation, polarization, and migration as well as astrogliosis and microglia/astrocyte interaction.
Highlights
Theiler’s murine encephalomyelitis (TME) represents a well-established animal model for the primary and secondary progressive form of multiple sclerosis (MS; [1,2,3,4,5])
MMP12 has been shown to cleave a wide range of myelin and extracellular matrix molecules in vitro, and the upregulation of MMP12 has been demonstrated in MS, TME, and experimental autoimmune encephalomyelitis [6]
TME virus (TMEV) infection of Mmp12−/− mice leads to a reduced degree of demyelination, supporting the assumption that MMP12 substantially contributes to demyelination [6]
Summary
Theiler’s murine encephalomyelitis (TME) represents a well-established animal model for the primary and secondary progressive form of multiple sclerosis (MS; [1,2,3,4,5]). Degenerative changes predominate in infected neurons and oligodendrocytes, leading to axonal loss and demyelination, whereas infected microglia/macrophages and astrocytes secrete numerous cytokines and chemokines including interferon (IFN) α/β, IL-1, IL-12, tumor necrosis factor (TNF), IL-10, and monocyte chemotactic protein 1, thereby inducing an antiviral immune response [4,6,20,21,22,23,24,25,26,27,28,29] In this context, matrix metalloproteinases (MMPs) play an important role since they are involved in physiological processes such as angiogenesis, axonal growth, myelinogenesis, and neurogenesis as well as in pathological conditions such as inflammation, demyelination, and blood-brain barrier breakdown [30]. Infection of matrix-metalloproteinase-12-deficient (Mmp12−/−) mice with the BeAn strain of TMEV resulted in an improved clinical course, reduced demyelination, as well as a reduced intralesional number of microglia/macrophages in the spinal cord [6] These observations suggest that MMP12 has an essential impact on the development and/or progression of demyelinating diseases of the CNS
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