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

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.