Cathepsin L inhibition enhances microglial CX3CR1 expression in EAE

Abstract

Cathepsin L (CatL), a lysosomal cysteine protease, is highly expressed in antigen-presenting cells and plays a role in the processing of autoantigens. It is widely expressed throughout the CNS and is associated with microglia-driven neuroinflammatory responses. Previous studies suggest that inhibition of catL activity may offer therapeutic potential for the treatment of multiple sclerosis. The aim of this study was to investigate the effects of a selective catL inhibitor [CC(=O)c1cccc(NC(=O)c2cnc3sccn3c2=O) c1] on microglia in mice immunized for experimental autoimmune encephalomyelitis (EAE). The catL inhibitor was administered intraperitoneally for five consecutive days from the onset of clinical signs of disease. Mononuclear cells were isolated from the spinal cord (SC) of EAE rats and analysed by flow cytometry. Given that this was the first in vivo application of this inhibitor, hepatotoxicity and nephrotoxicity were also investigated. The administered catL inhibitor reduced the infiltration of the SC by CD4+ T lymphocytes. On the other hand, the proportion of CD11b+ cells among the mononuclear cells isolated from the SC was higher in the treated EAE mice. CatL inhibitor decreased the proportion of CD45high cells among CD11b+ cells, most likely monocyte-derived macrophages that infiltrated the SC and increased the proportion of CD45low/int cells among CD11b+ cells, which correspond to microglia. The proportion of neuroprotective CX3CR1+ cells among microglial cells was significantly higher in treated mice than in untreated EAE mice. These findings reinforce the hypothesis that catL could serve as a potential therapeutic target for treating multiple sclerosis