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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 μg/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-NH 2 , 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.

frontiers in pharmacology

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