Abstract
Recombinant human growth differentiation factor 15 (rhGDF15) affects dendritic cell (DC) maturation. However, whether GDF15 is expressed in DCs and its roles and signaling in DCs remain largely unknown. It is unclear whether GDF15-DCs can induce immune tolerance in heart transplantation (HT). This study aims to understand the impact of endogenous GDF15 on DC's development, function, underlying molecular mechanism including circular RNA (circRNA). This study will also explore GDF15-DC-mediated immune modulation in HT. Bone marrow (BM) derived DCs were cultured and treated to up- or down regulate GDF15 expression. Phenotype and function of DCs were detected. Expression of genes and circRNAs was determined by qRT-PCR. The signaling pathways activated by GDF15 were examined. The impact of GDF15 treated DCs on preventing allograft immune rejection was assessed in a MHC full mismatch mouse HT model. Our results showed that GDF15 was expressed in DCs. Knockout of GDF15 promoted DC maturation, enhanced immune responsive functions, up-regulated malat-1 circular RNA (circ_Malat 1), and activated the nuclear factor kappa B (NFκB) pathway. Overexpression of GDF15 in DCs increased immunosuppressive/inhibitory molecules, enhanced DCs to induce T cell exhaustion, and promoted Treg generation through IDO signaling. GDF15 utilized transforming growth factor (TGF) β receptors I and II, not GFAL. Administration of GDF15 treated DCs prevented allograft rejection and induced immune tolerance in transplantation. In conclusion, GDF15 induces tolerogenic DCs (Tol-DCs) through inhibition of circ_Malat-1 and the NFκB signaling pathway and up-regulation of IDO. GDF15-DCs can prevent alloimmune rejection in HT.
Highlights
Heart transplantation (HT) is the gold standard for the treatment of patients with end stage heart failure or severe coronary artery disease
We aimed to investigate the role of endogenous GDF15 in dendritic cell (DC) development and DC-mediated immune tolerance induction, and signaling pathways activated by GDF15
We demonstrated that overexpression of GDF15 promoted exhaustive DCs to induce T cell exhaustion and enhanced Treg generation that was IDOdependent
Summary
Heart transplantation (HT) is the gold standard for the treatment of patients with end stage heart failure or severe coronary artery disease. Despite improvements in shortterm outcomes, long-term patient and graft survival remain suboptimal due to the toxic side effects associated with longterm use of immunosuppressive drugs. An ideal treatment able to induce allograft-specific tolerance in transplant recipients, which enables long-term graft survival while avoiding the need for immunosuppression and its associated adverse effects, is urgently needed. More detailed elucidation of new immune suppressive molecules and signaling pathways will help develop innovative new immune rejection treatment strategies for HT. DCs play a crucial role in determining the fate of a transplanted organs: rejection or acceptance by a host, depending on their immune suppressive or immune responsive function [1]. Immune tolerance induction still needs to be further explored and improved
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