TLR4 and TLR9 Polymorphisms Effect on Inflammatory Response in End-Stage Renal Disease Patients

Abstract

Toll-like receptors (TLRs) playa key role in the response of innate and adaptive immune system to microbial and endogenous ligands. Inflammation is a common feature in end-stage renal disease (ESRD) patients; however, the mechanisms/factors triggering the inflammatory process are still poorly clarified. Our aim was to analyze the impact of the c.-1486T>C and c.896A>G polymorphisms in TLR9 and TLR4 genes, respectively, on the inflammatory response of ESRD patients. Clinical and laboratory evaluation was carried out on 184 ESRD patients. Polymerase chain reaction followed by restriction fragmens length polymorphisms (PCR-RFLP) was employed for genotyping of TLR-4 c.896A>G and TLR-9 c.-1486T>C polymorphisms. The prevalence of AA and AG of TLR4 c.896A>G polymorphism in ESRD patients was 97.8% and 2.2%, respectively. None of the individuals showed a homozygous TLR4 polymorphism. Concerning the TLR9 c.-1486T>C polymorphism, we found that ESRD patients showed a prevalence of TC and CC genotypes of 57.1% and 20.6%, respectively. We found that the heterozygous patients for the TLR4 c.896A>G polymorphism presented an increased level in lymphocyte count, a decrease in neutrophil/lymphocyte ratio and in serum levels of hepcidin. Regarding the TLR9 c.-1486T>C polymorphism, we found that it is associated with decreased white blood cell and neutrophil counts, ferritin and CRP serum levels, and with an increase in serum levels of creatinine. Our data suggest that the presence of the studied polymorphisms is associated with a decreased inflammatory response in ESRD patients under hemodialysis, and, thus its presence might have beneficial effects in ESRD patients. Moreover, our data provide new insights in the role of TLR polymorphisms in renal disease, which might have impact in the near future for the development of innovative therapies.

Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

“…Furthermore, TLRs have also been implicated as potential drivers of cisplatin-induced pathologies and toxicities, including AKI [ 55 , 218 , 219 ]; renal injury [ 220 , 221 , 222 ]; allodynia [ 218 ]; and ototoxicity [ 223 ]. As demonstrated by TLR-deficient animal models [ 55 , 218 , 219 ] and polymorphisms in humans [ 224 , 225 , 226 , 227 ], the absence or improper function of TLRs may influence susceptibility and severity of pathologies affecting the renal system. Therefore, immunopathological consequences and renoprotective abilities originating from TLR activation in CIAKI are described.…”

Pathomorphological Manifestations and the Course of the Cervical Cancer Disease Determined by Variations in the TLR4 Gene

“…The TLR4 receptor is likely to be associated with several diseases because of the range of ligands (both pathogen-related and endogenous) identified as agonists of TLR4 [ 25 ]. TLR4 is linked to a range of diseases with potential treatments targeting the TLR4 pathway [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. TLR4 activation can not only cause antitumor immunity but also, conversely, promote immunosuppression and influence tumor growth [ 68 ].…”

No Major Effect of Innate Immune Genetics on Acute Kidney Rejection in the First 2 Weeks Post-Transplantation

“…Single nucleotide polymorphisms (SNPs) in CASP1, CRP, IL1B, IL2, IL6, IL6R, IL10, TGFB, and TNF can increase or decrease the protein production and/or function of these pro-and antiinflammatory mediators in vitro (Kroeger et al, 1997;Turner et al, 1997;Awad et al, 1998;Hoffmann et al, 2001;Dunning et al, 2003;Hall et al, 2004;Trompet et al, 2008;Wang et al, 2009) or serum/plasma concentrations in vivo (Fishman et al, 1998;Grainger et al, 1999;Galicia et al, 2004;Smith et al, 2008;Lacruz-Guzmán et al, 2013). In addition, SNPs in the MyD88dependent TLR signaling pathway affect innate immune responses to vaccines (Ovsyannikova et al, 2011) and susceptibility to infection or disease in vivo (Taniguchi et al, 2013;Santos-Martins et al, 2014). Therefore, these innate immunogenetic markers may serve as predictors of acute rejection post-kidney transplantation.…”