Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

Abstract

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients.

Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

“…The pro-oxidant and pro-inflammatory effects of PTUB are related to the intricate signaling cascade of ROS/ MAPK pathways in diverse cell models [14][15][16]. Nonetheless, data about therapeutic targeting PCS induced MAPK activation in HASMC are still lacking.…”

“…Apoptotic bodies derived from HASMCs may also act as crystal nucleation for calcium deposition [13]. The underlying mechanism involved in PTUB have been attributed by various signaling pathways including ROS/c-Jun N-terminal kinase (JNK)/P38/mitogen-activated protein kinases (MAPK) [14], aryl hydrocarbon receptor (AhR)/nuclear factor kappa B (NFκB)/ MAPK [15], and ROS-activated NF-κB/extracellular signal-regulated kinases (ERK)/ JNK cascades [16]. In vitro, IS accentuated Pi-induced VSMC calcification and osteogenic transition through increasing Pit-1 expression [17] and oxidative stress [17].…”

The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

“…These data suggest that the UTs that accumulate in brain tissue during CKD might impact the polarization of infiltrated monocytes/macrophages. In line with this observation, IS has been reported to directly induce monocyte-mediated inflammation and ROS production in THP-1 monocytes via the NADPH oxidase and MAPK pathways [ 123 ] and display direct pro-inflammatory effects in vitro via activation of the NF-kB and MAPK pathways in macrophages differentiated from THP-1 cells [ 127 ]. In addition, in a recent study performed on in vitro THP-1 cell cultures, IS was reported to promote CD163 expression and transition to macrophages with the hallmarks of classical M1 (IL-6, CCL2, COX2) and alternative M2 (IL-10, PPARγ, TGF-β, TIMP-1) phenotypes via AhR/Nrf2 activation.…”

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.…”