Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation by regulation of β-catenin and YAP pathways

Abstract

Evidence has been shown that indoxyl sulfate (IS) could impair kidney and cardiac functions. Moreover, macrophage polarization played important roles in chronic kidney disease and cardiovascular disease. IS acts as a nephron-vascular toxin, whereas its effect on macrophage polarization during inflammation is still not fully elucidated. In this study, we aimed to investigate the effect of IS on macrophage polarization during lipopolysaccharide (LPS) challenge. THP-1 monocytes were incubated with phorbol 12-myristate-13-acetate (PMA) to differentiate into macrophages, and then incubated with LPS and IS for 24 h. ELISA was used to detect the levels of TNFα, IL-6, IL-1β in THP-1-derived macrophages. Western blot assay was used to detect the levels of arginase1 and iNOS in THP-1-derived macrophages. Percentages of HLA-DR-positive cells (M1 macrophages) and CD206-positive cells (M2 macrophages) were detected by flow cytometry. IS markedly increased the production of the pro-inflammatory factors TNFα, IL-6, IL-1β in LPS-stimulated THP-1-derived macrophages. In addition, IS induced M1 macrophage polarization in response to LPS, as evidenced by the increased expression of iNOS and the increased proportion of HLA-DR+ macrophages. Moreover, IS downregulated the level of β-catenin, and upregulated the level of YAP in LPS-stimulated macrophages. Activating β-catenin signaling or inhibiting YAP signaling suppressed the IS-induced inflammatory response in LPS-stimulated macrophages by inhibiting M1 polarization. IS induced M1 macrophage polarization in LPS-stimulated macrophages via inhibiting β-catenin and activating YAP signaling. In addition, this study provided evidences that activation of β-catenin or inhibition of YAP could alleviate IS-induced inflammatory response in LPS-stimulated macrophages. This finding may contribute to the understanding of immune dysfunction observed in chronic kidney disease and cardiovascular disease.

Pre-existing serum indoxyl sulfate and COVID-19 outcomes in patients undergoing hemodialysis: A retrospective cohort study

“…Consistent with previous experimental [11,24] and clinical [12,25] findings, our study demonstrated a direct correlation between serum IS levels and the concentrations of proinflammatory markers, such as CRP, IL-6, MCP-1, and TNF-α. These findings provide further evidence of the proinflammatory effects of IS in patients undergoing HD.…”

“…Indoxyl sulfate (IS), a uremic toxin generated by gut microbiota from dietary tryptophan, has emerged as a potential key mediator of chronic inflammation in CKD [10]. It has been shown to activate inflammatory pathways and promote oxidative stress, contributing to the systemic inflammation observed in patients treated with maintenance HD [10][11][12][13]. Elevated levels of IS have been associated with various adverse outcomes in CKD, including cardiovascular disease and mortality [14,15].…”

Involvement of chronic inflammation via monocyte chemoattractant protein‐1 in uraemic cardiomyopathy: a human biopsy study

“…In this study, as M2 macrophages were rarely observed in the UCM heart (data not shown), the majority of macrophages were thought to be M1 macrophages. This finding suggested that M1 macrophages might be polarized by a uraemic toxin 27 and the activation of PlGF/Flt‐1 signalling, and the sustained pro‐inflammatory environment lead to the development of interstitial fibrosis, 14,16,25,26 which is consistent with the degree of interstitial fibrosis to be higher with a longer duration of RRT.…”

Does Indoxyl Sulfate Have a Role in Uremic Pruritus? A Laboratory and Interventional Study

“…IS can activate and upregulate several meditators involved in itching such as protease-activated receptor-2, [38][39][40] cannabinoid receptor type 1, 41,42 NLRP3 Inflammasome, 43,44 endothelin-1, 45,46 signal transducer and activator of transcription 3, 47,48 astrocyte activity, 49,50 NADPH oxidase, 51,52 transient receptor potential vanilloid 1, 53,54 Intercellular Adhesion Molecule 1 (ICAM-1), 55,56 Transforming growth factor-β (TGF-β), 57,58 and macrophage. 59,60 In addition, IS can downregulate antiitching mediators such as nuclear factor E2-related factor 2. 61,62 Also, IS is a neurotoxin and can initiate neuroinflammation and induce cognitive impairment and behavioral abnormality, [63][64][65][66][67] which can exacerbate itching.…”