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

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.

Cathepsin K maintains the number of lymphocytesin vivo

“…Interestingly, both these cathepsins have previously been described to regulate lymphopoiesis. For instance, CTSL has been shown to be a negative regulator of B lymphopoiesis (18), as well as CD4 + T lymphopoiesis (19) and CTSS is involved in Th17 differentiation (20). Furthermore, both CTSL and CTSS and other cathepsins like cathepsin B (CTSB) have been implicated in different stages of endosomal processing during antigen presentation (21), and failure to correctly present antigens in the context of MHC Class II or CD1d molecules may lead to defective Th2 lymphocyte responses (21).…”

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

“…Enrichment of MHC II molecules within late endocytic structures has consistently been seen in splenic DCs of CatS-deficient mice [97]. Pharmacological or genetic inhibition of CatS results in defective TLR2 signaling in the P. gingivalis LPS-exposed DCs, indicating CatS may be involved in innate immune responses [10,42].…”

“…e unique immune-stimulatory activity of DC stems from their ability to efficiently capture and present antigens and optimally express cytokines after P. gingivalis LPS stimulation [42]. Naïve DCs are found in large numbers in gingival tissues, and DCs are matured in the inflamed gingival tissues from patients with periodontitis [43] which particularly serve as immune stimulators [44].…”

“…Evidence-Based Complementary and Alternative Medicine promotes differentiation of 17 cells in response to P. gingivalis LPS-exposed DCs through protease-activated receptor (PAR) 2-dependent IL-6 production [42]. Subsequently, the increased IL-6 triggers the differentiation of 17 cells, illustrating the significant role of CatS in the differentiation of 17 cells, after the exposure to P. gingivalis LPS [42]. Considering the critical roles of CatS in adaptive immune responses through promoting the differentiation of both 1 and 17 cells in periodontitis, CatS may provide a novel therapeutic target for treatment of periodontitis.…”

Are Porphyromonas gingivalis Outer Membrane Vesicles Microbullets for Sporadic Alzheimer’s Disease Manifestation?

“…This association encompasses immunocompromised individuals whose susceptibility to infection increases and promotes pathobiomes to develop. In periodontitis and related conditions, as discussed by Olsen et al [20] and Dekita et al [21], dysbiosis is achieved through manipulation of the host's adaptive immune system involving cellular immunological responses, specifically of T-and B-cells. However, the common neuropathological characteristics amyloid-beta (A␤) and hyperphosphorylated tau binding neurofibrillary tangles (NFTs) remain the same irrespective of the course of the AD disease process.…”