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Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis.

ABSTRACT: Members of the Toll-like receptor (TLR) family serve as pathogen sensors and participate in local autoimmune responses. This study found a correlation between glomerular injury and TLR expression by analysing BXSB/MpJ-Yaa (BXSB-Yaa) lupus model mice. In isolated glomeruli, the mRNA expression of several TLRs was higher in BXSB-Yaa mice than in healthy control BXSB mice. In particular, the expression of Tlr8 and its downstream cytokines was markedly increased. In mouse kidneys, TLR8 protein and mRNA localized to podocytes, and TLR8 protein expression in the glomerulus was higher in BXSB-Yaa mice than in BXSB mice. In BXSB-Yaa mice, the glomerular levels of Tlr8 mRNA negatively correlated with the glomerular levels of podocyte functional markers (Nphs1, Nphs2, and Synpo) and positively correlated with urinary albumin levels. Furthermore, the glomerular and serum levels of miR-21, a putative microRNA ligand of TLR8, were higher in BXSB-Yaa mice than in BXSB mice. The urinary levels of Tlr8 mRNA were also higher in BXSB-Yaa mice than in BXSB mice. In conclusion, the overexpression of TLR8 correlates with the progression of podocyte injury in glomerulonephritis. Thus, altered levels of urinary Tlr8 mRNA might reflect podocyte injury.

SUBMITTER: Kimura J

PROVIDER: S-EPMC4252901 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis.

Kimura Junpei J Ichii Osamu O Miyazono Kosuke K Nakamura Teppei T Horino Taro T Otsuka-Kanazawa Saori S Kon Yasuhiro Y

Scientific reports 20141203

Members of the Toll-like receptor (TLR) family serve as pathogen sensors and participate in local autoimmune responses. This study found a correlation between glomerular injury and TLR expression by analysing BXSB/MpJ-Yaa (BXSB-Yaa) lupus model mice. In isolated glomeruli, the mRNA expression of several TLRs was higher in BXSB-Yaa mice than in healthy control BXSB mice. In particular, the expression of Tlr8 and its downstream cytokines was markedly increased. In mouse kidneys, TLR8 protein and m ...[more]

PMID: 25468389

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Project description:WHAT WE ALREADY KNOW ABOUT THIS TOPIC:Toll-like receptor 7 responds to elevated single-stranded RNA by increasing cytokine production. Sepsis is characterized by elevated plasma levels of tissue damage (and pathogen)-associated molecular patterns, including RNA. WHAT THIS ARTICLE TELLS US THAT IS NEW:Using murine models of bacterial sepsis, knockout of the Toll-like receptor 7 resulted in lower mortality and cytokine levels and less end-organ injury. Therefore, Toll-like receptor 7, which mediates innate immune response, contributes to harm in experimental sepsis. BACKGROUND:Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. METHODS:Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. RESULTS:The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24?h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. CONCLUSIONS:Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

Dataset Information

Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis.

Publications

Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis.

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