Critical role of KLK6 in the pathogenesis of Multiple Sclerosis

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It results in neurological impairments. One of animal model is myelin oligodendrocyte glycoprotein (MOG)- induced experimental autoimmune encephalomyelitis (EAE), which is characterized by paralysis and immune cell infiltration in the CNS. We have previously reported that a serine protease, Kallikrein 6 (KLK6), is produced by exclusively mature oligodendrocytes in the CNS, and that KLK6 is up-regulated in oligodendrocytes after spinal cord injury and EAE. However, the function of KLK6 in the pathogenesis of MS has not been fully understood.Here we report that KLK6 is involved in onset of EAE via BBB breakdown. To investigate the role of KLK6 in demyelination, we examined the effect of KLK6 on onset of EAE in KLK6 knock out (KO) mice. KLK6 KO mice exhibited an altered EAE progression characterized by delayed onset and progression of clinical symptoms as compared to wild-type mice. Histological study with luxol fast blue also revealed a decreased number of infiltrating inflammatory cells in spinal cord with EAE, suggesting that absence of KLK6 suppressed infiltration of peripheral inflammatory cells into the CNS with EAE. We next examined the effect of KLK6 on BBB permeability by evans blue dye injection. KLK6 KO mice showed much suppression of BBB permeability compared to wild-type mice. Finally we found that activation of Matrix metalloprotease-9 was inhibited in KLK6 KO mice with EAE. These results suggest that KLK6 play a crucial role of the pathogenesis of EAE.