Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model

Background:Homoharringtonine(HHT)is an effective anti-inflammatory,anti-viral,and anti-tumor protein synthesis inhibitor that has been applied clinically.Here,we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods:Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver,kidney,and hematology.A mouse heart transplantation model was constructed,and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis,immunostaining,and bulk RNA sequencing analysis.The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells(Tregs)differentiation.Results:HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo.Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days(P<0.001)without non-immune toxicity.The allografts had long-term survival after continuous HHT treatment for 28 days.HHT significantly reduced lymphocyte infiltration in the graft,and interferon-γ-secreting CD4^(+)and CD8^(+)T cells in the spleen(P<0.01).HHT significantly increased the number of peripheral Tregs(about 20%,P<0.001)and serum interleukin(IL)-10 levels.HHT downregulated the expression of T cell receptor(TCR)signaling pathway-related genes(CD4,H2-Eb1,TRAT1,and CD74)and upregulated the expression of IL-10 and transforming growth factor(TGF)-βpathway-related genes and Treg signature genes(CTLA4,Foxp3,CD74,and ICOS).HHT increased CD4^(+)Foxp3^(+)cells and Foxp3 expression ex vivo,and it enhanced the inhibitory function of inducible Tregs.Conclusions:HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels,thereby promoting mouse heart allograft acceptance.These findings may have therapeutic implications for organ transplant recipients,particularly those with viral infections and malignancies,which require a more suitable anti-rejection medication.

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases:A biomarker and potential therapeutic target

Triggering receptor expressed on myeloid cells-1(TREM-1)is a member of the immunoglobulin superfamily.As an amplifier of the inflammatory response,TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival.TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders.More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases.There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease.This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury,renal fibrosis,diabetic nephropathy,immune nephropathy,and renal cell carcinoma.