Advertisement

Inflammation Research

, Volume 67, Issue 5, pp 371–374 | Cite as

Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade

  • Ryo Okada
  • Xinwen Zhang
  • Yuka Harada
  • Zhou Wu
  • Hiroshi Nakanishi
Short Communication

Abstract

Objective

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.

Methods

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.

Keywords

Cathepsin H Cathepsin S Dendritic cell Microglia Experimental autoimmune encephalomyelitis Th1 cell 

Notes

Acknowledgements

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).

References

  1. 1.
    Allan ERO, Yates RM. Redundancy between cysteine cathepsins in murine experimental autoimmune encephalomyelitis. PLoS One. 2015;10:e0128945.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lafuse WP, Brown D, Castle L, Zwilling BS. IFN-γ increases cathepsin H mRNA levels in mouse macrophages. J Leukoc Biol. 1995;57:663–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Faraco J, Lin L, Kornum BR, et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 2013;9:e1003270.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bühling F, Kouadio M, Chwieralski CE, Kern U, Hohlfeld JM, Klemm N, et al. Gene targeting of the cysteine peptidase cathepsin H impairs lung surfactant in mice. PLoS One. 2011;6:e26247.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yamasaki R, Lu H, Butovsky O, et al. Differential roles of microglia and monocytes in the inflammed central nervous system. J Exp Med. 2014;211:1533–49.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Garcia-Cattaneo A, Gobert FX, Muller M, et al. Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling. Proc Natl Acad Sci USA. 2012;109:9053–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B. Cutting edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-β. J Immunol. 2006;177:7505–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Aging Science and Pharmacology, Faculty of Dental SciencesKyushu UniversityFukuokaJapan
  2. 2.Center of Implant Dentistry, School of SomatologyChina Medical UniversityShenyangChina
  3. 3.Department of Chemistry, School of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
  4. 4.Department of Pharmacology, Faculty of Pharmaceutical SciencesYasuda Women’s UniversityHiroshimaJapan

Personalised recommendations