Quantitation of the RANK-RANKL axis in primary biliary cholangitis

Ana Lleo, Zhaolian Bian, Haiyan Zhang, Qi Miao, Fang Yang, Yanshen Peng, Xiaoyu Chen, Ruqi Tang, Qixia Wang, Dekai Qiu, Jingyuan Fang, Cristina Sobacchi, Anna Villa, Luca Di Tommaso, Massimo Roncalli, M. Eric Gershwin, Xiong Ma, Pietro Invernizzi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

There is substantial data that suggests an abnormality of innate immunity in patients with primary biliary cholangitis (PBC) which includes the transcription factor nuclear factor-kB (NF-kB) and well as downstream inflammatory signaling pathways. In addition, Immuno-Chip analysis has identified a novel PBC-associated locus near the receptor activator of NF-kB ligand (RANKL) gene. Based on these observations, we investigated the role of the RANKL axis in the liver of patients with PBC compared to controls. We used immunohistochemistry to quantitate liver expression of RANKL, its receptor (RANK), and importantly the decoy receptor osteoprotegerin (OPG), including a total of 122 liver samples (PBC = 37, primary sclerosing cholangitis = 20, autoimmune hepatitis = 26, chronic hepatitis B = 32 and unaffected controls = 7). In addition, we studied RANKL-RANK-OPG co-localization in CD4 and CD8 T cells, B cells, dendritic cells, macrophages, NK, NKT cells, hepatocytes, and cholangiocytes. We report herein that RANK is constitutively expressed by cholangiocytes in both unaffected and diseased liver. However, cholangiocytes from PBC express significantly higher levers of RANK than either the unaffected controls or liver diseased controls. CD4, CD8 and CD19 cells with in the portal areas around bile ducts in PBC express significantly higher levels of RANKL compared to controls. Importantly, the overall hepatic RANKL level and the ratio of hepatic RANKL/OPG correlated with disease severity in PBC. In conclusion, our data indicate a role of RANK-RANKL axis in the innate immune activation in PBC and we hypothesize that the damaged cholangiocytes, which express high levels of RANK, lead to the recruitment of RANKL positive cells and ultimately the classic portal tract infiltrates.

Original languageEnglish (US)
Article numbere0159612
JournalPLoS One
Volume11
Issue number9
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Lleo, A., Bian, Z., Zhang, H., Miao, Q., Yang, F., Peng, Y., Chen, X., Tang, R., Wang, Q., Qiu, D., Fang, J., Sobacchi, C., Villa, A., Di Tommaso, L., Roncalli, M., Gershwin, M. E., Ma, X., & Invernizzi, P. (2016). Quantitation of the RANK-RANKL axis in primary biliary cholangitis. PLoS One, 11(9), [e0159612]. https://doi.org/10.1371/journal.pone.0159612