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Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4 + FoxP3 + Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44 high CD62L low effector T cells while augmenting CD4 + FoxP3 + Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4 + FoxP3 + Tregs, but not CD4 + FoxP3 - T cells, in vivo and in vitro. Furthermore, we found that CD206 + subset of F4/80 + CD11b + macrophages expressed a higher level of mTNF-α than their CD206 - counterparts while PF increased mTNF-α expression on CD206 + macrophages in vitro and in vivo. In vitro studies showed that mTNF-α + M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α - counterparts, whereas the effects of mTNF-α + M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis., (Copyright © 2021 Elsevier Inc. All rights reserved.)