Paeoniflorin ameliorates murine lupus nephritis by increasing CD4+Foxp3+ Treg cells via enhancing mTNFα-TNFR2 pathway

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^highCD62L^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.

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