Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3-7) in Klk6+/+ mice but not in Klk6-/- mice. Interestingly, anti-MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti-MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme-linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.

Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain

“…It is known that suppression of KLK6 reduces the expression levels of inflammatory cytokines, chemokines, and their receptors. 52 Interestingly, these oligodendrocyte-only related genes are in module 36, which is significantly changed by DTMP back to the naı¨ve expression pattern. The expression of these genes is significantly reversed towards the naı¨ve state with recoveries larger than 80%.…”

Molecular architecture of the mouse nervous system

“…Of mature oligodendrocytes, the spinal cord-enriched MOL3, expressing the serine protease Klk6 was the most distinct. Klk6 was recently implicated in the pathogenesis of experimental autoimmune encephalomyelitis, a model of multiple sclerosis in mice (Bando et al, 2018).…”

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

“…These data underlie KLK6 as an attractive target for novel molecules that could inhibit its proteolytic activity as a treatment for various cancers (32)(33)(34). Finally, numerous studies indicated that KLK6 may also be involved in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and others (35)(36)(37)(38)(39)(40)(41). For example, raising neutralizing KLK6 antibodies in mice exerted overall beneficial effects in models of multiple sclerosis and CNS inflammatory disease, suggesting that selectively inhibiting KLK6 is not expected to be considerably toxic.…”