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Phosphatidic Acid Promoting the Generation of Interleukin‐17A Producing Double‐Negative T Cells by Enhancing mTORC1 Signaling in Lupus.
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- Author(s): Li, Wenjing; Tang, Xiaojun; Zheng, Yuanyuan; Xu, Xuefeng; Zhao, Nan; Tsao, Betty P.; Feng, Xuebing; Sun, Lingyun
- Source:
Arthritis & Rheumatology; Jul2024, Vol. 76 Issue 7, p1096-1108, 13p- Subject Terms:
PHOSPHOLIPID analysis; IN vitro studies; FLOW cytometry; PROTEINURIA; PEARSON correlation (Statistics); T cells; T-test (Statistics); DATA analysis; POLYMERASE chain reaction; IMMUNOGLOBULINS; ENZYME-linked immunosorbent assay; SYSTEMIC lupus erythematosus; CELLULAR signal transduction; MANN Whitney U Test; DESCRIPTIVE statistics; MICE; METABOLITES; CELL culture; ANIMAL experimentation; LIQUID chromatography; ELECTROSPRAY ionization mass spectrometry; MASS spectrometry; PHOSPHOLIPASES; ONE-way analysis of variance; STATISTICS; PHOSPHOTRANSFERASES; DATA analysis software; INTERLEUKINS; B cells; RAPAMYCIN; CELL separation - Source:
- Additional Information
- Abstract: Objective: The goal was to investigate the role and intracellular regulatory mechanisms of double‐negative T (DNT) cells in the pathogenesis of systemic lupus erythematosus (SLE). Methods: DNT cells were assessed in murine models, patients with SLE, and controls using flow cytometry (FCM). DNT cells from either resiquimod (R848) or vehicle‐treated C57BL/6 (B6) mice were cultured with B cells from R848‐treated mice to explore functions. Differential mechanistic target of rapamycin (mTOR) pathway signaling in DNT cells measured using FCM and quantitative polymerase chain reaction was validated by rapamycin inhibition. Candidate lipid metabolites detected using liquid chromatography with electrospray ionization mass spectrometry/mass spectrometry were functionally assessed in DNT cell cultures. Results: DNT cells were markedly increased in both spontaneous and induced mouse lupus models and in patients with SLE. Expanded DNT cells from R848‐treated B6 mice produced elevated interleukin (IL)‐17A and IgG with increased germinal center B (GCB) cells. Expansion of DNT cells associated with activation of mTORC1 pathway that both IL‐17A levels and the number of DNT cells exhibited dose‐dependent reduction with rapamycin treatment. Lipidomics studies revealed differential patterns of lipid metabolites in T cells of R848‐treated mice. Among candidate metabolites, elevated phosphatidic acid (PA) that was partially controlled by phospholipase D2 increased the expression of the mTORC1 downstream target p‐S6 and positively expanded IL‐17A–producing DNT cells. Similarly, elevated proportions of circulating DNT cells in patients with SLE correlated with disease activity and proteinuria, and IL‐17A secretion was elevated after in vitro PA stimulation. Conclusion: The accumulation of PA in T cells could activate the mTORC1 pathway, promoting DNT cell expansion and IL‐17A secretion, resulting in GCB cell abnormalities in lupus. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Arthritis & Rheumatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Abstract:
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