Protease-mediated regulation of host immune system and application as therapeutic targets

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In this study, we investigated the nature and function of both host-and bacteria-derived proteases in host immune system. Cathepsin E (catE) and gingipains were treated as a host-derived endolysosomal protease and bacterial proteases, respectively. The obtained results are as follows : (i) CatE differentially regulated the nature and function of dendritic cells and macrophages, (ii) CatE deficiency caused impairment of autophagy in macrophages manifesting mitochondria dysfunction and enhanced oxidative stress, (iii) Endogenous Cat E expression levels were positively associated with the growth arrest and metastasis reduction of tumor cells in vivo and the concomitant increase of tumor-associated activated macrophages in tumor microenvironment, (iv) CatE specifically induced apoptosis in tumor cells without affecting normal cells in vitro by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface, (v) Peptide-aptamer-based inhibitors and activators of CatE was generated by cDNA display techniques, (vi) Atherosclerosis progression in apolipoprotein E-knockout mice was accelerated by P. gingivalis infection, which was mediated by selective proteolysis of apolipoprotein B-100 by Arg-gingipain (Rgp), (vii) A risk for preterm birth and fetal death in pregnant mice was enhanced by P. gingivalis infection and inhibited by combination treatment of Rgp and Kgp inhibitors, (iii) A newly developed peptide analogue inhibiting both Rgp and Kgp suppressed most of the pethogenicity of P. gingivalis.