Redundancy between Cysteine Cathepsins in Murine Experimental Autoimmune Encephalomyelitis

Abstract

The cysteine cathepsins B, S, and L are functionally linked to antigen processing, and hence to autoimmune disorders such as multiple sclerosis. Stemming from several studies that demonstrate that mice can be protected from experimental autoimmune encephalomyelitis (EAE) through the pharmacologic inhibition of cysteine cathepsins, it has been suggested that targeting these enzymes in multiple sclerosis may be of therapeutic benefit. Utilizing mice deficient in cysteine cathepsins both individually and in combination, we found that the myelin-associated antigen myelin oligodendrocyte glycoprotein (MOG) was efficiently processed and presented by macrophages to CD4+ T cells in the individual absence of cathepsin B, S or L. Similarly, mice deficient in cathepsin B or S were susceptible to MOG-induced EAE and displayed clinical progression and immune infiltration into the CNS, similar to their wild-type counterparts. Owing to a previously described CD4+ T cell deficiency in mice deficient in cathepsin L, such mice were protected from EAE. When multiple cysteine cathepsins were simultaneously inhibited via genetic deletion of both cathepsins B and S, or by a cathepsin inhibitor (LHVS), MHC-II surface expression, MOG antigen presentation and EAE were attenuated or prevented. This study demonstrates the functional redundancy between cathepsin B, S and L in EAE, and suggests that the inhibition of multiple cysteine cathepsins may be needed to modulate autoimmune disorders such as multiple sclerosis.

Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody–Drug Conjugates

“…Concomitantly, the degree of compensation by the different cathepsins for the cleavage of the VC linker can also vary. For example, we found that immune (27)(28)(29). Dubowchik and colleagues posited that other enzymes in liver extracts might contribute to the faster digestion rate observed with lysosomal extracts versus purified cathepsin B (7).…”

Quantitative Proteome Analysis of Brain Subregions and Spinal Cord from Experimental Autoimmune Encephalomyelitis Mice by TMT‐Based Mass Spectrometry

“…Anatomically, EAE‐affected brains were found to be highly expressing CD14 in many regions such as SpC and CB . The lysosomal protein Ctss is responsible for MHC‐II processing, and knockout of Ctss leads to a lesser MHC‐II expression and MOG antigen presentation, in addition to protection from EAE . Hexb functions as a glycosyl hydrolase inside the lysosome and its dysfunction leads to neurodegenerative diseases.…”

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

“…It is to be noted here that several isoforms of cathepsin L have also been observed in specific cell types due to alternative splicing of mRNA transcripts and alternative translation [4,[37][38][39][40][41].Molecules 2020, 25, 698 2 of 40 variety of highly invasive forms of cancer is also now well established and has been a subject of elegant reviews elsewhere [25][26][27]. Unfortunately, several overlapping and redundant functions of cathepsin L have also emerged [5,[28][29][30]. It is therefore critically important that its functional biology in both normal and disease-specific cell types be clearly annotated before significant resources are directed in drug discovery endeavors.…”

“…This review elaborates on the recently developed small molecule inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.Molecules 2020, 25, 698 2 of 41 also now well established and has been a subject of elegant reviews elsewhere [25][26][27]. Unfortunately, several overlapping and redundant functions of cathepsin L have also emerged [5,[28][29][30]. It is therefore critically important that its functional biology in both normal and disease-specific cell types be clearly annotated before significant resources are directed in drug discovery endeavors.…”