Cathepsin L inhibition prevents murine autoimmune diabetes via suppression of CD8(+) T cell activity.
BACKGROUND
Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet β cells. To determine whether specific lysosomal proteases might influence the outcome of a T cell-mediated autoimmune response, we examined the functional significance of cathepsin inhibition on autoimmune T1D-prone non-obese diabetic (NOD) mice.


RESULTS
Here it was found that specific inhibition of cathepsin L affords strong protection from cyclophosphamide (CY)-induced insulitis and diabetes of NOD mice at the advanced stage of CD8(+) T cell infiltration via inhibiting granzyme activity. It was discovered that cathepsin L inhibition prevents cytotoxic activity of CD8(+) T cells in the pancreatic islets through controlling dipeptidyl peptidase I activity. Moreover, the gene targeting for cathepsin L with application of in vivo siRNA administration successfully prevented CY-induced diabetes of NOD mice. Finally, cathepsin L mRNA expression of peripheral CD8(+) T cells from NOD mice developing spontaneous T1D was significantly increased compared with that from control mice.


CONCLUSIONS
Our results identified a novel function of cathepsin L as an enzyme whose activity is essential for the progression of CD8(+) T cell-mediated autoimmune diabetes, and inhibition of cathepsin L as a powerful therapeutic strategy for autoimmune diabetes.
Yamada
Akiko
A
Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Ishimaru
Naozumi
N
Arakaki
Rieko
R
Katunuma
Nobuhiko
N
Hayashi
Yoshio
Y
D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D056668:Cathepsin L / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD
D056668:Cathepsin L