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Mitochondria Activity and CXCR4 Collaboratively Promote the Differentiation of CD11c+ B Cells Induced by TLR9 in Lupus

  • Sung Hoon Jang (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Joo Sung Shim (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Jieun Kim (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Eun Gyeol Shin (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Jong Hwi Yoon (Department of Microbiology, Yonsei University College of Medicine) ;
  • Lucy Eunju Lee (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Ho-Keun Kwon (Department of Microbiology, Yonsei University College of Medicine) ;
  • Jason Jungsik Song (Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine)
  • Received : 2024.06.03
  • Accepted : 2024.06.12
  • Published : 2024.08.31
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Abstract

Lupus is characterized by the autoantibodies against nuclear Ags, underscoring the importance of identifying the B cell subsets driving autoimmunity. Our research focused on the mitochondrial activity and CXCR4 expression in CD11c+ B cells from lupus patients after ex vivo stimulation with a TLR9 agonist, CpG-oligodeoxyribonucleotide (ODN). We also evaluated the response of CD11c+ B cells in ODN-injected mice. Post-ex vivo ODN stimulation, we observed an increase in the proportion of CD11chi cells, with elevated mitochondrial activity and CXCR4 expression in CD11c+ B cells from lupus patients. In vivo experiments showed similar patterns, with TLR9 stimulation enhancing mitochondrial and CXCR4 activities in CD11chi B cells, leading to the generation of anti-dsDNA plasmablasts. The CXCR4 inhibitor AMD3100 and the mitochondrial complex I inhibitor IM156 significantly reduced the proportion of CD11c+ B cells and autoreactive plasmablasts. These results underscore the pivotal roles of mitochondria and CXCR4 in the production of autoreactive plasmablasts.

Keywords

Acknowledgement

We are grateful to all the individuals who participated in the study. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT) (grant number RS-2023-00251155 to JJS and 2019R1A6A1A03032869 to HK).

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