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GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis.

ABSTRACT: Sepsis is a common critical illness in ICU and always a great difficulty in clinical treatment. GPR43 (G protein-coupled receptor 43) participates in regulating appetite and gastrointestinal peptide secretion to modulate fat decomposition and formation. However, the biological contribution of GPR43 on inflammation of sepsis has not been previously investigated. We investigated the mechanisms of GPR43 gene, which plays a possible role in distinguishing sepsis and contributes to the pathogenesis of sepsis-induced inflammatory reaction. Furthermore, we performed studies with mice induced to sepsis by Cecal Ligation and Puncture (CLP), Knockout GPR43 (GPR43-/-) mice, and Wild Type (WT) mice induced with CLP. In addition, lung tissues and cell samples were analyzed by histology, Quantitative Polymerase Chain Reaction (Q-PCR), Enzyme-linked Immunosorbent (ELISA) Assay, and western blot. GPR43 agonist could significantly reduce inflammation reactions and trigger lung injury in mice with sepsis. As for GPR43-/- mice, the risks of sepsis-induced inflammatory reactions and corresponding lung injury were promoted. On the one hand, the up-regulation of GPR43 gene reduced ROS mitochondrial damage to inhibit inflammatory reactions via the inactivation of NLRP3 Inflammasome by PPARγ/ Nox1/EBP50/ p47phox signal channel. On the other hand, the down-regulation of GPR43 promoted inflammatory reactions in vitro model through the acceleration of ROS-dependently mitochondrial damage by PPARγ/ Nox1/EBP50/ p47phox/ NLRP3 signal channel. These findings indicate that the inhibition of GPR43 as a possible important factor of sepsis may shed lights on the mechanism of sepsis-induced inflammation reaction.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8507289 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVES:Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. DESIGN:Prospective case-control study. SETTING:Academic Medical Center and Veterans Affairs Hospital. PATIENTS:Uninfected control patients (n = 20) and septic ICU patients (n = 37). INTERVENTIONS:Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. MEASUREMENTS AND MAIN RESULTS:Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. CONCLUSIONS:Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.

Project description:BackgroundRecent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI).MethodsWe isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function.ResultsA total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney.ConclusionAn elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

Project description:ObjectiveThis study aims to analyze the changes of fecal short chain fatty acids (SCFAs) content and gut microbiota composition in sepsis associated encephalopathy (SAE) mice, further evaluating the effect of SCFAs on cognitive function and the underlying mechanism in SAE mice.MethodsA total of 55 male adult C57BL/6 mice (2-3 months of age, 20-25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15). Seven days after surgery, fecal samples were collected for microbiota composition and SCFA analysis from 6 mice in each group randomly. Behavioral test was applied to assess cognitive impairment at the same time. After that, mice were sacrificed and brain tissue was harvested for inflammatory cytokines analysis.ResultsThe levels of acetic acid (.57 ± 0.09 vs 2.00 ± 0.24, p < 0.001) and propionic acid (.32 ± 0.06 vs .66 ± 0.12, p = 0.002) were significantly decreased in the CLP group compared with the sham group. The administration of SCFAs significantly increased the levels of acetic acid (1.51 ± 0.12 vs. 0.57 ± 0.09, p < 0.001) and propionic acid (0.54 ± 0.03 vs. 0.32 ± 0.06, p = 0.033) in CLP+SCFAs group compared with CLP group. Relative abundance of SCFAs-producing bacteria, including Allobaculum (0.16 ± 0.14 vs. 15.21 ± 8.12, p = 0.037), Bacteroides (1.82 ± 0.38 vs. 15.21 ± 5.95, p = 0.002) and Bifidobacterium (0.16 ± 0.06 vs. 2.24 ± 0.48, p = 0.002), significantly decreased in the CLP group compared with the sham group. The behavioral tests suggested that cognitive function was impaired in SAE mice, which could be alleviated by SCFAs pretreatment. ELISA tests indicated that the levels of IL-1β, IL-6, and TNF-α were elevated in SAE mice and SCFAs could lower them. However, the GPR43 antagonist, GLPG0974, could reverse the cognitive protective effect and anti-neuroinflammation effect of SCFAs.ConclusionOur study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE.

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GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis.

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