| First Author | Liang CL | Year | 2021 |
| Journal | Biochem Pharmacol | Volume | 185 |
| Pages | 114434 | PubMed ID | 33513343 |
| Mgi Jnum | J:309242 | Mgi Id | MGI:6757616 |
| Doi | 10.1016/j.bcp.2021.114434 | Citation | Liang CL, et al. (2021) Paeoniflorin ameliorates murine lupus nephritis by increasing CD4(+)Foxp3(+) Treg cells via enhancing mTNFalpha-TNFR2 pathway. Biochem Pharmacol 185:114434 |
| abstractText | 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-gamma, 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-alpha than their CD206(-) counterparts while PF increased mTNF-alpha expression on CD206(+) macrophages in vitro and in vivo. In vitro studies showed that mTNF-alpha(+) M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-alpha(-) counterparts, whereas the effects of mTNF-alpha(+) 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 mTNFalpha-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. |
