Abstract

BackgroundOridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts.MethodsThe cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro.ResultsOri with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression.ConclusionsOur findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.

Highlights

  • Oridonin (Ori), a natural ent-kaurane diterpenoid, is the major bioactive ingredient of Rabdosia rubescens, which has been widely applied in traditional Chinese and Japanese medicine for multiple diseases [1, 2]

  • NLRP3 is a cytoplasmic sensor in immune cells, like dendritic cells (DCs), macrophages, and T cells [19], and can detect a variety of stimuli signals, including danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), important participants in innate and adaptive immune responses [20, 21]

  • According to the ISHLT grading-score system, the grafts from the control group showed high levels of inflammatory infiltration and moderate or severe myocyte damage, whereas all isografts scored 0 and Ori-treated grafts scored 0–1 (p < 0.0001). These results demonstrated that Ori protected against acute in vivo allograft rejection

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Summary

Introduction

Oridonin (Ori), a natural ent-kaurane diterpenoid, is the major bioactive ingredient of Rabdosia rubescens, which has been widely applied in traditional Chinese and Japanese medicine for multiple diseases [1, 2]. The subsequent NLRP3 inflammasome assembly and activation [19, 22] promotes autophagy, gasdermin Dassociated pyroptosis [23, 24], and cleavage of pro-IL-1b and proIL-18 to form functional IL-1b and IL-18 [25]. This induces pyroptotic cell death [23] and reduces T-cell proliferation [26] and helper T (Th) cell differentiation [21, 27, 28]. We investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts

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