Phytochemicals as modulators of dendritic cell functions: implications for tolerogenic cell-based therapy

Dendritic cells (DCs) constitute a heterogeneous population of immune cells that acting as antigen presenting cells link innate and adaptive immune responses. Their functions are mainly dictated by microenvironmental cues, enabling them to either maintain immune tolerance or initiate robust humoral and cellular immune responses. While DCs are important for orchestrating immune responses, accumulating evidence suggests that aberrant DC activation contributes to the pathogenesis of autoimmune and chronic inflammatory diseases, making them promising targets for therapeutic modulation. Modulating DC functionality therefore represents a potent strategy to attenuate excessive inflammation in such conditions. Plant-derived bioactive compounds, or phytochemicals, are structurally diverse secondary metabolites with established anti-inflammatory and immunomodulatory properties. This review consolidates current <i>in vitro</i>, <i>in vivo</i>, and <i>in silico</i> findings on ten well-characterized phytochemicals including curcumin, 6-gingerol, 6-shogaol, resveratrol, epigallocatechin-3-gallate, quercetin, apigenin, capsaicin, berberine and ginsenosides, which have the capacity to modulate DC phenotype and function. Notably, these phytochemicals can skew DCs toward a tolerogenic phenotype, characterized by reduced expression of antigen presenting and co-stimulatory molecules, diminished pro-inflammatory cytokine secretion, and enhanced regulatory T cell induction. Mechanistic insights reveal convergence on key signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) in DCs. <i>In silico</i> studies further predict interactions of these compounds with various molecular targets, providing a structural basis for their immunoregulatory effects. Furthermore, studies using preclinical models of autoimmune and inflammatory diseases have demonstrated that these phytochemicals can attenuate disease severity, likely through DC modulation. Given their multifaceted immunomodulatory capacity, phytochemicals hold promise both as adjuvant therapies in DC-mediated autoimmune diseases and as agents for generating tolerogenic DCs for cell-based immunotherapies.