4.7 Article

Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis

Journal

FRONTIERS IN PHARMACOLOGY
Volume 8, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2017.00470

Keywords

lipopolysaccharide derived from Porphyromonas gingivalis; Cathepsin S; dendritic cells; IL-6; Th17 cells

Funding

  1. [16K11478]
  2. [16H05848]
  3. [15H05015]
  4. Grants-in-Aid for Scientific Research [16H05848, 16K11478] Funding Source: KAKEN

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Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4(+) T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS). The population of CD11c(+) DCs was significantly increased in the splenic marginal zone (MZ) locally of wild-type (DBA/2) mice with splenomegaly but not in that of CatS deficient (CatS(-/-)) mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal). Similarly, the population of Th17(+)CD4(+) T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS(-/-) mice after PgLPS exposure. Furthermore, the increase in the Th17(+) CD4(+) T cell population paralleled increases in the levels of CatS and IL-6 in CD11c(+) cells in the splenic MZ. In isolated primary splenic CD11c(+) cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS(-/-) mice after direct stimulation with PgLPS (1 mu g/ml), and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL), the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR) 2 in the isolated splenic CD11c(+) cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c(+) cells was completely abolished by pre-treatment with FSLLRY-NH2, a PAR2 antagonist, as well as Akti, a specific inhibitor of Akt. These findings indicate that CatS plays a critical role in driving splenic DC-dependent Th17 differentiation through the upregulation of IL-6 by activating PAR2 after exposure to components of periodontal bacteria. Therefore, CatS-specific inhibitors may be effective in alleviating periodontitis-related immune/inflammation.

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