Abstract
Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4/80+CD11b+CD206+ M2-like macrophages with no any significant effect on F4/80+CD11b+CD86+ M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4/80+Arg1+ subset while decreasing the percentage of F4/80+iNOS+ subset. Importantly, TGP treatment increased the percentage of both F4/80+CD11b+PD-L1+ and F4/80+CD11b+PD-L2+ subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages in vitro while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS/IFN-γ in vitro, indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages in vivo. Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4/80+CD11b+CD206+ and F4/80+CD11b+PD-L2+ macrophages through IL-4/STAT6/PD-L2 signaling pathway.
Highlights
Lupus nephritis (LN) is one of the most common complications in patients with systemic lupus erythematosus and represents a leading cause of end-stage renal failure [1]
Macrophage phenotypes and functions directly impact the progression and prognosis of lupus nephritis. This present study demonstrated that few PD-L1+ and PD-L2+ macrophages infiltrated in the kidney of mice with pristane-induced lupus nephritis
Total glucosides of paeony (TGP) treatment induced both PD-L1+ and PD-L2+ macrophages with less renal infiltration of iNOS+ macrophages, thereby ameliorating lupus nephritis in pristanetreated mice
Summary
Lupus nephritis (LN) is one of the most common complications in patients with systemic lupus erythematosus and represents a leading cause of end-stage renal failure [1]. LN is a complex autoimmune and inflammatory disease resulting from sustained imbalance between pro- and anti-inflammatory immune responses. The substantial infiltration of inflammatory cells in the kidney is a morphologic hallmark of human and experimental lupus nephritis. It is generally accepted that macrophages are the main infiltrating immune cells and play a unique role in the immune-based pathogenesis of lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis [4]. A number of studies have demonstrated that inhibiting macrophage infiltration or promoting macrophage M2 polarization is beneficial in the context of chronic kidney disease [5,6,7]. In parallel with effects of PD-Ls on macrophages, adoptive transfer of PD-L2+ M2 macrophages delayed the progression of murine experimental autoimmune encephalomyelitis (EAE) [12]. In view of the crucial roles for macrophages in the pathogenesis of LN, it is necessary to explore the mechanisms underlying macrophage activation and to seek an efficient therapeutic strategy of treating LN via rebalancing macrophage activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
