Uremic toxins are conditional danger- or homeostasis-associated molecular patterns

Abstract

We mined novel uremic toxin (UT) metabolomics/gene databases, and analyzed the expression changes of UT receptors and UT synthases in chronic kidney disease (CKD) and cardiovascular disease (CVD). We made the following observations: 1) UTs represent only 1/80th of human serum small-molecule metabolome; 2) Some UTs are increased in CKD and CVD; 3) UTs either induce or suppress the expression of inflammatory molecules; 4) The expression of UT genes is significantly modulated in CKD patients, and coronary artery disease (CAD) patients; 5) The expression of UT genes is upregulated by caspase-1 and TNF-alpha pathways but is inhibited in regulatory T cells. These results demonstrate that UTs are selectively increased, and serve as danger signal-associated molecular patterns (DAMPs) and homeostasis-associated molecular patterns (HAMPs) that modulate inflammation. These results also show that some UT genes are upregulated in CKD and CAD via caspase-1/inflammatory cytokine pathways, rather than by purely passive accumulation.

Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells

“…We have previously reported that LPC could induce innate immune signatures in HAECs, resulting in prolonged EC activation [54]. To examine the hypothesis that IL-35 and IL-10 could block innate immune signatures in HAECs, we performed gene set enrichment analysis (GSEA) [55].…”

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses—Inflammations and Cancers Can Have High Genomic Risks

“…As mentioned above, for the first time we propose a novel concept that DDCFs and DDRFs can act as nuclear sensors (Wang L. et al, 2016 ) for organelle stresses, which is a part of cellular sensor cross-talking network including classical DAMP receptors such as Toll-like receptors (Yang et al, 2008 ), caspase-1/Nod-like receptors and inflammasomes (Yin et al, 2013 ), conditional DAMPs receptors and our newly proposed homeostasis-associated molecular pattern receptors (Wang X. et al, 2016 ; Li et al, 2017a ; Wang et al, 2017 ; Sun et al, 2018 ), and mitochondrial ROS (Li et al, 2013 , 2016 , 2017b ; Cheng et al, 2017 ).…”

“…We also found that pro-atherogenic endogenous metabolites lysophospholipids such as lysophosphatidylcholines (lysoPC) act as conditional DAMPs. We previously proposed that lysoPC bind to their intrinsic receptors (conditional DAMP receptors) (Wang X. et al, 2016 ; Shao et al, 2017 ; Sun et al, 2018 ), and induce mitochondrial reactive oxygen species (mitoROS) (Li et al, 2013 , 2016 , 2017a ; Cheng et al, 2017 ) to upregulate aortic endothelial cell activation genes via histone 3 lysine 14 acetylation-AP1-dependent pathway (Li et al, 2018 ). However, it is not clear whether DDCFs and DDRFs act as the nuclear sensor for intracellular organelle stress, a part of our newly proposed cellular sensor cross-talking network.…”

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

“…Several UTs could potentially act as ligands in the activation of TLRs (Hauser et al, 2008). In this case, Sun et al (2018) reported that UTs can serve as conditional pro-inflammatory DAMPs (danger signal-associated molecular patterns) or anti-inflammatory HAMPs (homeostasisassociated molecular patterns) and modulate inflammation. Consequently, classical DAMP receptors signaling activation such as TLRs, NLR-inflammasome-activated caspase-1 and other pro-inflammatory cytokines can elevate uremic toxins levels, as well as be inhibited by CD4 + Foxp3 + regulatory T cells (Sun et al, 2018).…”