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

Abstract

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

“…Selective inactivated BMDC A 2A Rs or activated non-BMDC A 2A Rs led to systemic inflammatory response, and increased the expression of CF, accordingly activated microglia, whereas selective reconstitution reversed the above phenomenon. CF, a potent endogenous cysteine protease inhibitor, was substantially up-regulated in regions of white matter rarefaction that occurred in various demyelinating diseases of the CNS [32,33]. In this study, we found that BMDC A 2A Rs suppressed CF-mediated microglia activated and non-BMDC A 2A Rs promoted CF-mediated microglia activated, which was consistent with our previous research [16].…”

Cystatin F Affects Natural Killer Cell Cytotoxicity

“…Cystatin F is also implicated in several pathological processes. It has been suggested to play a role in multiple sclerosis during the acute phase of demyelination ( 29 , 30 ), in polycythemia vera, a myeloproliferative disorder characterized by an increased proliferation of cells of myeloid lineages ( 31 ) and in chronic fatigue syndrome ( 32 ). Higher expression of the inhibitor correlates with the inflammatory processes associated with lung disorders ( 33 ).…”

Cathepsin C modulates myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis

“…We discovered that the Plp1 ‐over‐expressing mouse line ( Plp 4e/− ) and cuprizone mouse model showed worsened symptoms in our previous studies when CysF expression was eliminated, indicating that CysF has supporting role in the demyelinating mouse models which do not show hematopoietic cell infiltration in the lesions (Liang et al . ; Shimizu et al . ).…”

“…These results are consistent with previous data using Plp 4e/− and cuprizone model mice (Liang et al . ; Shimizu et al . ), suggesting that CatC plays a role during the early stage of inflammatory demyelinating disease.…”

“…A similar result was found in a cuprizone‐induced demyelination model, where the absence of the CysF gene and the resulting disinhibition of CatC aggravated the demyelination (Liang et al . ). CatC activity can be regulated by various mechanisms and is involved in inflammatory responses (Conus and Simon ); for example, the absence of the CysF gene increases the activity of CatC and enhances demyelination.…”