Abstract
Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.
Highlights
Www.nature.com/scientificreports molecular pattern molecules (PAMPs) and gingipain
To shed light on the mechanism underlying the progression of liver fibrosis caused by P.g.-odontogenic infection, the roles of hepatic stellate cells (HSCs) activation caused by P.g.- infection through gingipain and P.g.-derived LPS/lipoprotein stimulations in the process of liver fibrosis have been analyzed, especially focusing on transforming growth factor-β1 (TGF-β1) and Gal-3
HP group indicated significantly increased sirius red positive fibrosis areas (p < 0.05), [Fig. 2e]. These data suggest that P.g.-odontogenic infection aggravates inflammatory cell infiltration and liver fibrosis, in which TGF-β1/Smad and Gal-3 pathway are involved
Summary
Www.nature.com/scientificreports molecular pattern molecules (PAMPs) and gingipain (a trypsin like enzyme). PAMPs bind to specific receptors such as toll-like receptors (TLRs) and resulting in inducing periodontal inflammation[12]. Our group has demonstrated that HFD-induced NASH mouse model significantly increased toll-like receptor 2 (TLR2) expression in liver, suggesting increasing reactivity for P.g.-derived PAMPs10. TGF-β1 and Galectin-3 (Gal-3; a unique chimera-type β-galactoside-binding protein of the galectin family) are reported to be the key molecules for liver fibrosis through HSC activation[14,16,17]. To shed light on the mechanism underlying the progression of liver fibrosis caused by P.g.-odontogenic infection, the roles of HSC activation caused by P.g.- infection through gingipain and P.g.-derived LPS/lipoprotein stimulations in the process of liver fibrosis have been analyzed, especially focusing on TGF-β1 and Gal-3
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