IL-17A activated by Toll-like receptor 9 contributes to the development of septic acute kidney injury

Naito, Yasuhisa; Tsuji, Takayuki; Nagata, Soichiro; Tsuji, Naoko; Fujikura, Tomoyuki; Ohashi, Naro; Kato, Akihiko; Miyajima, Hiroaki; Yasuda, Hideo

doi:10.1152/ajprenal.00313.2019

Cited by 16 publications

(8 citation statements)

References 61 publications

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“…These results are in line with murine and clinical data (9, 44). IL-17A, which is the only inflammatory cytokine having significantly higher levels in the septic HFD-fed mice in our study, has been shown to contribute to kidney injury in CLP-induced sepsis, as knockout of IL-17A improved functional and morphological measures of AKI, and exogenous administration of IL-17A aggravated AKI (45). Data derived from septic-AKI patients and human cells stimulated ex vivo support the hypothesis that IL-17A drives AKI in sepsis (46).…”

Section: Discussionsupporting

confidence: 91%

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

Lewis¹,

Williams²,

Bruno³

et al. 2021

Shock

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Despite the known deleterious effects of obesity, clinical data indicate that overweight or obese patients experience higher rates of sepsis survival compared to normal and underweight patients; a phenomenon called the obesity paradox. Results from preclinical sepsis studies have not been able to replicate these findings. The objective of this study was to test the existence of the obesity paradox in a murine model of cecal slurry (CS)-induced sepsis with insulin-resistant diet-induced obese mice. Male C57BL/6 mice were provided high-fat (HFD) or low-fat (LFD) diets for 20 weeks. HFD-fed mice experienced higher rates of survival compared to LFD-fed mice after septic challenge induced by CS injection (66% vs. 25%, P ¼ 0.01, survival assessed for 14 days). Despite the survival advantage, HFD-fed mice had higher rates of positive bacterial cultures and increased markers of kidney injury. Circulating levels of IL-6, IL-1b, TNFa, and IL-23 were equivalent 24 h after CS-injection; however, IL-17A was uniquely increased in HFD-fed mice. While LFD-fed mice maintained euglycemia, HFD-fed mice were hyperglycemic 6 and 12 h after CS-injection. Stable isotope resolved metabolomics analysis of liver tissue showed diverging pathways of glucose utilization during sepsis, with LFD-fed mice significantly upregulating glycolytic activity and HFD-fed mice decreasing glucose entry into the TCA cycle. This murine study corroborates clinical data that obesity confers a survival benefit in sepsis, albeit at the expense of more significant organ injury. The mechanisms promoting survival in the obese remain unknown; however, this model appears to be well-poised to begin answering this question. Differences in glucose utilization are a novel target to investigate this paradox.

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Section: Discussionsupporting

confidence: 91%

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

Lewis¹,

Williams²,

Bruno³

et al. 2021

Shock

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“…Il17d plays a key role in the recruitment of human immune cells [ 31 ]. Studies have reported that Tlr9 caused acute injury by activating IL-17A [ 32 ]. In addition, the expression of genes such as Ccl6 ( C-C Motif Chemokine Receptor 6 ), Ccl9 ( C-C Motif Chemokine Receptor 9 ), Cxcl14 ( C-X-C Motif Chemokine Ligand 14 ) and Il21r ( interleukin 21 receptor ) were also significantly down-regulated after treatment with GFT505.…”

Section: Discussionmentioning

confidence: 99%

The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model

Liu

Zhao

et al. 2020

PLoS ONE

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Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Pparα, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgfα, Pdgfβ, Tgfβ1, Tgfβ2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH.

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“…TLR9-knockout mice have a reduced cytokine production, splenic apoptosis, and kidney injury in SI-AKI [204]. Furthermore, TLR9 knockout mice have lower levels of IL-17A and IL-1β after cecal ligation and puncture producing SI-AKI [205]. Administration of chloroquine, an inhibitor of endocytic TLRs (TLR3, TLR7, TLR8, TLR9), reduced sepsis-induced mortality and renal injury severity in SI-AKI.…”

Section: Sepsis-induced Akimentioning

confidence: 99%

Toll-Like Receptors in Acute Kidney Injury

Vázquez‐Carballo

Guerrero‐Hue

García‐Caballero

et al. 2021

IJMS

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Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition.

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IL-17A activated by Toll-like receptor 9 contributes to the development of septic acute kidney injury

Cited by 16 publications

References 61 publications

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model

Toll-Like Receptors in Acute Kidney Injury

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