Table 1.
Known human Toll‐like receptors, described agonists and potential involvement in SI‐AKI
| TLR | Example of ligands | Involvement in SI‐AKI |
|---|---|---|
| TLR1 | Triacylated lipopeptides | Pam3cys, an agonist of TLR1 complexed with TLR2 stimulates complement factor B (cfB) production in human proximal tubular cells. Experimental data suggest that this can contribute to SI‐AKI (Li et al. 2016) |
| TLR2 | Bacterial: Glycolipids, phenol‐soluble modulin, lipoprotein, lipoteichoic acid peptidoglycan. Viral: proteins from measles, CMV, HSV‐1. Fungal: lipoarabinomannan, zymosan. Potential endogenous: biglycan, histones, HMBG‐1, hyaluronan, heat‐shock proteins | TLR2‐deficient mice with CLP have less renal hypoxia (Castoldi et al. 2012). Neutralizing histones acting via TLR2 and TLR4 reduces plasma creatinine In murine endotoxemia (Allam et al. 2012). Activation of TLR2 may upregulate cfB that contributes to increased mRNA level of NGAL and KIM‐1 in polymicrobial murine sepsis (Zou et al. 2013). TLR2 inhibits HCO3− reabsorption in the medullary thick ascending limb in response to LPS (Good et al. 2010, 2012). Bacterial lipopeptide acts through TLR2 to increase protein permeability in cultured glomerular endothelial cells and podocytes (Pawar et al. 2009) |
| TLR3 | Viral double‐stranded RNA | Activation of TLR3 may upregulate cfB that contributes to increased mRNA level of NGAL and KIM‐1 in polymicrobial murine sepsis (Zou et al. 2013) |
| TLR4 | Bacterial: LPS. Fungal: Mannan. Viral: Protein from RSV. Potential endogenous: heparin sulphate, fibrinogen, biglycan, histones, HMBG‐1, hyaluronan, heat‐shock proteins | TLR4 mediates reduction in urine output and GFR in a sheep model of E. coli sepsis (Fenhammar et al. 2014). Sepsis causes TLR4 upregulation in the kidney and stimulation results in renal PMN infiltration, release of pro‐inflammatory cytokines and chemokines, glomerular endothelial swelling, tubular ion transport dysfunction and apoptosis. See text for further details and references |
| TLR5 | Bacterial flagellin | Flagellin causes a systemic inflammatory response and liver injury but no renal injury, estimated by change in plasma urea, in mice (Liaudet et al. 2002). TLR5 activation may protect against urinary infection (Andersen‐Nissen et al. 2007) |
| TLR6 | Interacts with TLR2 to recognize bacterial lipopeptides and fungal zymosan | Unknown |
| TLR7 | Single‐stranded RNA from, that is HIV and Influenza virus | TLR7 has been shown to activate B‐lymphocytes and contribute to glomerulonephritis in response to viral agonists (Pawar et al. 2007). Although not verified to be mediated completely by TLR7, AKI often develops in patients with severe influenza infection and this is associated with increased risk of dying (Pettila et al. 2011). |
| TLR8 | ssRNA, synthetic imidazoquinoline derivatives | Unknown. |
| TLR9 | Viral and bacterial CpG DNA motifs | Knockdown of TLR9 by siRNA reduced the increase in plasma creatinine and urea in response to polymicrobial sepsis in mice (Liu et al. 2012). TLR9 knockout reduced AKI in CLP‐induced septic mice (Dear et al. 2006, Yasuda et al. 2008). Possibly via stimulation by mitochondrial DNA (Tsuji et al. 2015) |
| TLR10 | Unknown | Unknown |