Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

Abstract

Indoxyl sulfate (IS) is a uremic toxin associated with increased prevalence of cardiovascular diseases (CVDs) in patients with chronic kidney disease. Despite the crucial role of uremia‐related immune dysfunction, a majority of studies attempting to elucidate its pathogenic role in CVD have focused on IS‐mediated endothelial dysfunction. Thus, we investigated the underlying molecular mechanisms involved in IS‐induced production of TNF‐α, a major cardiotoxic cytokine, by human macrophages. We found that crosstalk between the aryl hydrocarbon receptor (AhR), NF‐κB, and the suppressor of cytokine signaling (SOCS)2 is important for TNF‐α production in IS‐stimulated human macrophages. IS‐activated AhR rapidly associates with the p65 NF‐κB subunit, resulting in mutual inhibition of AhR and NF‐κB and inhibition of TNF‐α production at an early time point. Later, this repression of TNF‐α production is alleviated when SOCS2, a negative modulator of NF‐κB, is directly induced by IS‐activated AhR. In addition, once free of inhibition, activated AhR induces TNF‐α expression by interacting with AhR binding sites in the TNF‐α gene. Lastly, we confirmed decreased AhR and increased SOCS2 expression in monocytes of patients with end‐stage renal disease, indicating the activation of AhR. Taken together, our results suggest that IS‐induced TNF‐α production in macrophages is regulated through a complicated mechanism involving interaction of AhR, NF‐κB, and SOCS2.—Kim, H. Y., Yoo, T.‐H., Cho, J.‐Y., Kim, H. C., Lee, W.‐W. Indoxyl sulfate‐induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages. FASEB J. 33, 10844–10858 (2019). http://www.fasebj.org

Suppressed Hepatic Production of Indoxyl Sulfate Attenuates Cisplatin-Induced Acute Kidney Injury in Sulfotransferase 1a1-Deficient Mice

“…A previous study also reported that AhR was ubiquitinated and degraded by the proteasome system after binding to its ligand [24]. It has recently been reported that IS is an endogenous agonist of AhR [25][26][27][28]. AhR is a ligand-activated transcription factor involved in the biological detoxification of ligands [29].…”

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

“…In addition, IxS induces monocytic ROS production in an NADPH oxidase-dependent manner [82]. The IxS-induced TNF-α production in macrophages is regulated through a mechanism involving the interaction of AhR, NF-κB, and the suppression of cytokine signaling [83]. IxS also increases LPS-induced NF-κB nuclear translocation, ROS release and altered calcium concentrations in J774A.1 macrophages, mainly because of mitochondrial calcium overloading [84].…”

Indoxyl Sulfate-Mediated Metabolic Alteration of Transcriptome Signatures in Monocytes of Patients with End-Stage Renal Disease (ESRD)

“…Functional GSEA of monocytes from patients with ESRD identified the alteration of major metabolic pathways including glycolysis, oxidative phosphorylation, and fatty acid metabolism, as well as immune response-related pathways such as interferon-α and γ responses, the inflammatory response, and TNF-α signaling via NF-κB ( Figure 3 and Table S3 ). We and others have demonstrated that IS elicits immune responses by its binding to AhR in monocytes/macrophages [ 36 , 37 ]. Thus, identification of immune response-related pathways in GSEA was expected.…”

“…TNF-α is also considered an important pro-atherogenic cytokine in CVD [ 47 ]. In addition, IS is a potent endogenous ligand for AhR, and IS-stimulation of monocytes/macrophages results in increased production of TNF-α through a complicated regulation mechanism between AhR, NF-κB, and SOCS2 [ 16 , 36 ]. Chemokines and their receptors regulate migration of leukocytes under normal and inflammatory conditions.…”