Uncovering molecular mechanisms involved in the IL-37-mediated tolerogenic dendritic cells

Summary: Abstract Body: Mounting evidence suggests that therapies based on monocyte-derived tolerogenic dendritic cells (tolDCs) offer significant potential for treating autoimmune and chronic inflammatory diseases and preventing transplant rejection. In our previous work, adoptive transfer of hapten-sensitized DCs from mice expressing the human IL-37b isoform (IL-37tg) significantly reduced contact hypersensitivity in wild-type recipients, illustrating that IL-37 suppresses antigen-specific adaptive immune responses through the induction of tolDCs. In this study, we investigated the molecular mechanisms underlying IL-37-mediated tolDC induction. We observed that IL37 expression was markedly upregulated in human tolDCs generated by various pharmacological agents (e.g., vitamin D3, dexamethasone). Promotor-binding transcription profiling and siRNA-mediated knockdown identified VDR, CEBPB, AP1, and SOX9 as key transcription factors driving IL-37 induction in tolDCs. Gene expression analysis further revealed IL-37-mediated changes in immune genes (CXCL1, IL10), pathways (NFkB, IL10, CD40, HMGB1), and immunosuppressive miRNAs. Consistent with these findings, the knockdown of IL37 in vitamin D3 (VitD3)-treated tolDCs reversed their tolerogenic phenotype and enhanced their ability to stimulate allogeneic T cells, underscoring the role of IL-37 in VitD3-induced tolDC function. To explore their in vivo efficacy, we compared IL-37-expressing tolDCs with VitD3-treated tolDCs in suppressing GVHD. While IL-37-expressing human tolDCs provided sustained GVHD suppression for over a month, VitD3-treated human tolDCs had a limited response. Furthermore, exposing VitD3-treated tolDCs to proinflammatory cytokines (IL-6 and TNFα) lowered IL-37 levels and increased IL-12 expression, suggesting diminished in vivo efficacy under inflammatory conditions. Collectively, our findings identify IL-37 as a critical mediator of dendritic cell tolerance, providing new insights into the molecular pathways that govern tolDC induction and maintenance. Shahid H. Naikoo¹, Prasanna Vaddi¹, Yuchun Luo¹, Mayumi Fujita^{1, 2} 1. Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. 2. Dermatology, Denver VA Medical Center, Aurora, CO, United States. Adaptive and Auto-Immunity