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 Kruskalâ»Wallis test followed by Mannâ»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.