Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells

Br J Pharmacol. 2013 Jul;169(6):1305-21. doi: 10.1111/bph.12205.

Abstract

Background and purpose: Dietary indole derivatives, indole-3-carbinol (I3C) and diindolylmethane (DIM), possess anti-cancer properties and exhibit the characteristics of aryl hydrocarbon receptor (AhR) ligands. Because AhR activation has recently been shown to regulate T cell differentiation, we tested the hypothesis that I3C and DIM may mediate anti-inflammatory properties by promoting regulatory T cell (T-regs) differentiation while inhibiting Th17 cells.

Experimental approach: We investigated the therapeutic efficacy of I3C and DIM against experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The efficacy was evaluated based on clinical scores of paralysis, histopathology, serum cytokines and infiltration of T cells in the CNS. We next studied the mechanism of induction of T cells against myelin oligodendrocyte glycoprotein (MOG₃₅₋₅₅ ) peptide, both in vivo and in vitro, specifically investigating the differentiation of T-regs and Th17 cells, and determined if indoles were acting through AhR.

Key results: Pretreatment of EAE mice with I3C or DIM completely prevented the clinical symptoms and cellular infiltration into the CNS. Also, post-treatment of EAE with I3C or DIM proved highly effective in curtailing the overall severity of the disease. In addition, I3C or DIM promoted the generation of T-regs, while down-regulating the induction of MOG-specific Th17 cells. The regulation of FoxP3 induction and suppression of Th17 cells by indoles in vivo and in vitro were found to be AhR-dependent.

Conclusions and implications: Together, our studies demonstrate for the first time that I3C and DIM may serve as novel therapeutics to suppress neuroinflammation seen during MS through activation of AhR.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Basic Helix-Loop-Helix Transcription Factors / agonists
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / drug effects*
  • Central Nervous System / drug effects
  • Central Nervous System / immunology
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Female
  • Forkhead Transcription Factors / agonists
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / drug effects
  • Immunity, Cellular / drug effects
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / therapeutic use
  • Indoles / administration & dosage
  • Indoles / therapeutic use*
  • Injections, Intraperitoneal
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / metabolism
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Th17 Cells / pathology

Substances

  • Ahr protein, mouse
  • Anti-Inflammatory Agents, Non-Steroidal
  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Immunologic Factors
  • Indoles
  • Ligands
  • Receptors, Aryl Hydrocarbon
  • indole-3-carbinol
  • 3,3'-diindolylmethane