4.6 Article

Therapeutic effects of cationic liposomes on lupus-prone MRL/lpr mice are mediated via inhibition of TLR4-triggered B-cell activation

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ELSEVIER
DOI: 10.1016/j.nano.2021.102491

关键词

Toll-like receptor 4; B cell; Lupus nephritis; HMGB1 siRNA

资金

  1. National Natural Science Foundation of China [81773673]
  2. Zhejiang Provincial Natural Science Foundation of China [LGF19H300007]
  3. Key Laboratory of Ningbo, China [2016A22002]

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This study investigated the therapeutic effects of TAT-CLs-DHA/siRNA on lupus-prone MRL/Ipr mice and its impact on B cell responses. The results showed that TAT-CLs-DHA/siRNA suppressed the proliferation and activation of B cells through the TLR4 signaling pathway and significantly reduced lupus-related symptoms in the mice. Furthermore, the study revealed that TAT-CLs-DHA/siRNA modulated the B-cell intrinsic pathway by downregulating expression of certain molecules.
We previously reported that co-delivery of dihydroartemisinin and high mobility group box 1 (HMGB1) siRNAs, using cell penetrating peptide (TAT)-modified cationic liposomes (TAT-CLs-DHA/siRNA), resulted in promising activity for the treatment of inflammatory disease through TLR4 signaling pathway. In the current study, we further investigated the therapeutic effects of TAT-CLs-DHA/siRNA on lupus-prone MRL/Ipr mice and explored its effects on B cell responses. In vitro, we found that TAT-CLs-DHA/siRNA suppressed the proliferation and activation of B cells through the TLR4 signaling pathway. Following parenteral administration every 4 days, TAT-CLsDI IA/siRNA significantly reduced proteinuria, glomerulonephritis, serum anti-dsDNA antibody and secretion of interleukin (IL)-6, IL-10. IL-17 and IL-21. Moreover, Western blotting showed that TAT-CLs-DHA/siRNA modulated the B-cell intrinsic pathway by downregulating expression of HMGB1, TLR4, MyD88 and NF-kappa B. This co-delivery system thus represents a promising treatment option for lupus nephritis, and also highlights a novel target of lupus treatment through B cell TLR4 signal pathway. (C) 2021 Elsevier Inc. All rights reserved.

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