Microglial cystatin F expression is a sensitive indicator for ongoing demyelination with concurrent remyelination

Abstract

Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area.

Identification of a microglia phenotype supportive of remyelination

“…Since Ma et al (2011) found a positive correlation between microglia cystatin-F expression and the regenerative capacity of the CNS tissue in multiple MS models and MS spinal cords as well, the expression profile of this particular enzyme in our study further supports our claim that the principal function of microglia is support of regeneration.…”

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model

“…A broad spectrum of biological roles has been suggested for cystatins, including a role in protein catabolism, regulation of hormone processing and bone resorption, inflammation, antigen presentation, and T-cell dependent immune responses, and resistance to various bacterial and viral infections (Magister and Kos, 2013). Cystatins have been suggested to serve as modulators of the proteolytic system in several diseases (Magister and Kos, 2013), including demyelinating diseases (Ma et al, 2007, 2011; Sladkova et al, 2011; Duan et al, 2012). Cystatin F (Cys F), which belongs to the cystatin superfamily, is a cathepsin inhibitor.…”

“…The timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with the remyelination areas. Induction of Cys F ceased in chronic demyelination when the remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination (Ma et al, 2011). Predating our study, Cys F was identified as an up-regulated gene after lipopolysaccharide (LPS) stimulation of monocyte-derived dendritic cells (Hashimoto et al, 2000) and was independently designated as a cystatin-like metastasis-associated protein, the level of expression of which is correlated with metastatic potential in liver tumors (Morita et al, 2000).…”

“…Predating our study, Cys F was identified as an up-regulated gene after lipopolysaccharide (LPS) stimulation of monocyte-derived dendritic cells (Hashimoto et al, 2000) and was independently designated as a cystatin-like metastasis-associated protein, the level of expression of which is correlated with metastatic potential in liver tumors (Morita et al, 2000). We have described in detail the pattern of Cys F expression in microglia/macrophages in the CNS of several demyelinating animal models and in the spinal cord tissues of MS patients (Ma et al, 2011); however, the functional role of Cys F in demyelinating diseases of the CNS is unclear.…”

Microglia-Induced Activation of Noncanonical Wnt Signaling Aggravates Neurodegeneration in Demyelinating Disorders

“…7A and B). Heterozygous plp-transgenic (plp 4e/-) mice overexpressing the proteolipid protein gene (plp) closely mimic the failure of remyelination observed in chronic demyelinated lesions of MS (47). At 2 months of age, plp 4e/Ϫ mice have an abnormal paranodal structure (48).…”