Involvement of Commensal Bacteria may Lead to Dysregulated Inflammatory and Autoimmune Responses in a Mouse Model for Chronic Nonsuppurative Destructive Cholangitis
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We previously reported a mouse model of primary biliary cirrhosis (PBC)-like chronic nonsuppurative destructive cholangitis (CNSDC), in which frequent injections of Streptococcus intermedius induced CNSDC and autoantibody production. The present study was performed to verify the model by examining 1) the reappearance of the PBC-like CNSDC after lymphocyte transfer from model to naïve mice, 2) the involvement of autophagy, and 3) the influence of the strain difference.
Mice were inoculated with S. intermedius weekly for 8 weeks, then sacrificed to obtain samples. Spleen cells obtained from S. intermedius-inoculated mice were transferred to RAG2-/- mice.
CNSDC and elevated serum level of anti-gp210 titers were observed in S. intermedius-inoculated C57BL/6 mice, similar to the results of our previous report using BALB/c mice. Portal inflammation was induced in the livers of RAG2-/- mice by the transfer of spleen cells from S. intermedius-inoculated C57BL/6 mice. Among the inflammatory cells in the RAG2-/- mice, CD3-positive cells were predominant. Autophagosome-like structures were detected histologically, in the cytoplasm of infiltrated cells around the bile ducts in the livers of S. intermedius-inoculated both C57BL/6 and BALB/c mice. In S. intermedius-inoculated C3H/HeJ mice, inflammation in the portal area was less extensive than that in the hepatic parenchyma.
Bacterial component(s) and sequentially upregulated innate and acquired immune responses, accompanied by autophagy, might trigger CNSDC, via autoimmune mechanisms. Throughout the generation of bacteria-triggered PBC-like CNSDC, strain difference may influence the response to S. intermedius-inoculation in the liver.
KeywordsChronic nonsuppurative destructive cholangitis (CNSDC) primary biliary cirrhosis (PBC) bacteria innate immunity gp210 autophagy
Primary biliary cirrhosis
Pathogen-associated molecular patterns
Genome-wide association studies
Toll like receptor
Phosphate buffered saline
The authors thank Professor Takehiko Uchiyama (Tokiwa University) for profound discussion, Mr. Hideyuki Takeiri, Mrs. Noriko Sakayori, Mr. Mizuho Karita and Mr. Yasuhide Shigematsu for their skillful technical assistance, Dr. Yutaka Arimura and Mr. Hidehiro Ueshiba for their help with the series of bacterial inoculations in the mice, and Mr. Masamichi Yoshikawa for the intensive animal care. This work was financially supported in part by Grants-in-Aid for Scientific Research (C23590522 to I.H. and C21590496 to J.Y) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
The authors declare that we have no conflicts of interest.
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