Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade
The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
EAE was induced in CatH-deficient mice (CatH−/−) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35–55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes.
Results and conclusions
CatH−/− showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH−/− showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-β secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE.
KeywordsCathepsin H Cathepsin S Dendritic cell Microglia Experimental autoimmune encephalomyelitis Th1 cell
CatH−/− were kindly provided by Profs. Christoph Peters and Thomas Reinheckel (Albert-Ludwings-University Freiberg). This work was supported by Grants-in-Aid for Scientific Research (no. 26861555 to RO, no. 16H01340 to HN), MEXT, Japan, and a Grant from the National Natural Science Foundation of China (no. 81500858 to XZ).