Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation

Abstract

Aryl hydrocarbon receptor (AhR) regulates both innate and adaptive immune responses by sensing a variety of small synthetic and natural chemicals, which act as its ligands. AhR, which is expressed in dendritic cells (DCs), regulates the differentiation of DCs. However, effects of AhR on the differentiation of DCs are variable due to the heterogeneity of DCs in cell surface marker expression, anatomical location, and functional responses. The plasmacytoid DCs (pDCs), one of DC subsets, not only induce innate as well as adaptive immune responses by secreting type I interferons and pro-inflammatory cytokines, but also induce IL-10 producing regulatory T cell or anergy or deletion of antigen-specific T cells. We showed here that AhR ligands indoxyl 3-sulfate (I3S) and indole-3-carbinol (I3C) inhibited the development of pDCs derived from bone marrow (BM) precursors induced by FMS-like tyrosine kinase 3 ligand (Flt3L). I3S and I3C downregulated the expression of signal transducer and activator of transcription 3 (STAT3) and E2-2 (Tcf4). In mice orally treated with I3S and I3C, oral tolerance to dinitrofluorobenzene was impaired and the proportion of CD11c+B220+ cells in mesenteric lymph nodes was reduced. These data demonstrate that AhR negatively regulates the development of pDCs from BM precursors induced by Flt3L, probably via repressing the expression of STAT3.

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

“…The AhR regulates both innate and adaptive immune responses and is expressed in dendritic cells (DCs). The AhR inhibits the development of plasmacytoid DCs from bone marrow precursors induced by FMS-like tyrosine kinase-3 ligand (Flt3L), probably via inhibition of signal transducer and activator of transcription-3 (STAT3) expression [79]. The study by Ghimire et al suggested an anti-inflammatory and tolerizing effect of IxS on human DCs [80].…”

Modulation of immunity by tryptophan microbial metabolites

“…This effect was attributed to the suppression of STAT5 and STAT6 phosphorylation, which are transcription factors involved in Th2 differentiation. I3S can also induce T cell apoptosis, or programmed cell death, by upregulating the expression of pro-apoptotic proteins (192). Other indole derivatives, IAld and IPA, have also been shown to modulate immune responses by regulating T-cell function (193,194).…”