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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02524

Toll-like receptor-mediated activation of CD39 internalization in BMDCs leads to extracellular ATP accumulation and facilitates P2X7 receptor activation

ronglan zhao1,  Jinjuan Qiao1, Xumei Zhang2, Yansong Zhao3, Xiangying Meng1,  Deming Sun4 and  Xiaoxiang Peng1*
  • 1Department of Laboratory Medicine, Weifang Medical University, China
  • 2Department of Pathology, Affiliated Hospital of Weifang Medical University, China
  • 3Department of Ophthalmology, Affiliated Hospital of Weifang Medical University, China
  • 4Doheny Eye Institute (DEI), United States

Toll-like receptors (TLRs) trigger innate immune responses through their recognition of conserved molecular ligands of either endogenous or microbial origin. Although activation, function and signaling pathways of TLRs were already well studied, their precise function in specific cell types, especially innate immune cells, needs to be further clarified. In this study, we showed that when significantly decreased amounts of membrane CD39, an ATP-degrading enzyme, were detected in lipopolysaccharide (LPS)-treated bone marrow-derived DCs (BMDCs), Cd39 mRNA expression and whole-cell CD39 expression were at the same levels as those in untreated BMDCs. Further experiments demonstrated that the downregulation of membrane CD39 expression in LPS-treated BMDCs was mediated by endocytosis leading to membrane-exposed CD39 downregulation, which was positively associated with decreased enzymatic activity in ATP metabolism and increased extracellular ATP accumulation. The accumulated ATP promoted intracellular calcium accumulation and IL-1β production in BMDCs through P2X7 signaling activation. Further research revealed that not only LPS but also other TLR ligands, excluding polyI:C, induced CD39 internalization in BMDCs and that the MyD88 pathway was critical in this process. The results suggested that the activation of CD39 internalization in DCs induced by a TLR ligand caused increased ATP accumulation, leading to P2X7 receptor activation that mediated a proinflammatory effect. Considering the strong modulatory effect of extracellular ATP accumulation on the immune response and inflammation, the manipulation of membrane CD39 expression on DCs may have implications on the regulation and treatment of inflammatory responses.

Keywords: Toll-like receptor ligands, CD39, internalization, P2X7R, ATP

Received: 17 Jul 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 zhao, Qiao, Zhang, Zhao, Meng, Sun and Peng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Xiaoxiang Peng, Department of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong Province, China,