Abstract
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-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.
Highlights
Periodontitis, a common oral chronic multi-bacterial infection, results from the relevant bacteria and their components entering the body through the bloodstream
We examined the involvement of Cathepsin S (CatS) in the response of the spleen after systemic exposure to PgLPS, a TLR2 agonist, as the spleen is susceptible to infection
The significant increase in the number of CD11c+ dendritic cells (DCs) paralleled the increase in the TLR2 expression in CD11c+ DCs in the splenic marginal zones (MZs) of wildtype mice after systemic exposure to PgLPS, indicating that DCs in the splenic MZ sensitively respond to TLR2 activation (Figures 1E–H)
Summary
Periodontitis, a common oral chronic multi-bacterial infection, results from the relevant bacteria and their components entering the body through the bloodstream. Porphyromonas gingivalis (P. gingivalis) is the major periodontal bacteria (Seymour et al, 2007), and its lipopolysaccharide derived from P. gingivalis (PgLPS) induces executive pro-inflammatory responses through various types of cells, including macrophages, leptomeningeal cells, microglia and fibroblasts (Wu et al, 2008; Liu et al, 2013; Wu and Nakanishi, 2015; Li et al, 2016). The spleen is the largest secondary immune organ (SLO) for regulating the immune response and inflammation (Lind and Lind, 2012; Zhao et al, 2015) and is susceptible to infection because of its anatomical structures (Cadili and de Gara, 2008; Getts et al, 2011; Tarantino et al, 2011). The marginal zones (MZs), in which abundant dendritic cells (DCs) and macrophages interface with T-cell zones (Bajénoff et al, 2008; Ruddle and Akirav, 2009), are considered therapeutic targets for modulating innate and adaptive immunity (Zhao et al, 2015)
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