Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: A crucial role for aryl hydrocarbon receptor

Abstract

Macrophages are versatile phagocytic cells in immune system with immunoregulatory functions. However, the removal of apoptotic cells by macrophages is disturbed in systemic lupus erythematosus (SLE). Aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor with diverse effects on immune response. Indole-3-carbinol (I3C) is an AhR agonist which has been implicated as a beneficial factor in regulating inflammation and cytokine expression in murine models of SLE. However, the molecular mechanisms are not thoroughly studied. Here, we aimed to investigate the ex vivo effects of I3C on polarization of monocyte-derived macrophages (MDMs) in SLE patients and the expression of regulatory cytokines upon AhR activation. MDMs from 15 newly diagnosed SLE patients and 10 normal subjects were induced by Jurkat apoptotic bodies (JABs) and treated with I3C. I3C enhanced the nuclear accumulation of AhR among MDMs of SLE patients and altered the expression of AhR target genes including CYP1A1, IL1- β, IDO-1 and MRC-1. The imbalanced expression of pro- and anti- inflammatory cytokines (IL-10, IL-12, TGFβ1, TNFα, IL-23, IL-6 and IFN-γ) was compensated in response to I3C. AhR activation was also associated with the overexpression of M2 markers (CD163) and downregulation of M1 markers (CD86). Thus, macrophages are activated alternatively in response to I3C. The obtained data indicate that I3C-mediated AhR activation possess immunoregulatory effects on macrophages of SLE patients by exerting an obvious downregulation in the expression of pro-inflammatory and overexpression of anti-inflammatory cytokines. Therefore, AhR could be targeted and further investigated as a choice of anti-inflammatory therapies for autoimmune disorders such as SLE.

Keywords:

• Aryl hydrocarbon receptor
• indole-3-carbinol
• macrophage polarization
• monocyte-derived macrophages
• systemic lupus erythematosus

Acknowledgments

The authors thank Dr Marie Saghaeian-Jazi, Dr Ayyoob Khosravi, Dr Sareh Zhand, Mr Mohammad Shariati and Mrs Haydari for their scientific and technical support.

Disclosure statement

The authors declare no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the article.

Additional information

Funding

This work was supported by Gorgan School of Advanced Technologies in Medicine, Golestan University of Medical Sciences [grant number 931128255], [grant number 31078693122410].