Autophagy Is Impaired in Neutrophils from Streptozotocin-Induced Diabetic Rats

Kuwabara, Wilson Mitsuo Tatagiba; Curi, Rui; Alba-Loureiro, Tatiana Carolina

doi:10.3389/fimmu.2017.00024

Cited by 15 publications

(14 citation statements)

References 72 publications

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“…It has been reported that alterations in mitochondrial function cause a decrease in the membrane potential (Δψ m ), affecting the metabolic activity and causing a decrease in the amount of ATP, with the consequent low production capacity of ROS. The alteration of the mitochondrial processes results in an altered phagocytic capacity and chemotaxis of the neutrophils 52 , 53 . When bone marrow isolated neutrophils were exposed to LPS, there was a slight increase of the Δψ m loss.…”

Section: Resultsmentioning

confidence: 99%

Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6

Magaña‐Guerrero¹,

Domínguez-López²,

Martinez-Aboytes³

et al. 2017

Sci Rep

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The mesenchymal stem cells obtained from human amniotic membrane (hAMSC) possess immunosuppressive functions through soluble factors such as prostanoids and proteins; thus, they have been proposed to ameliorate inflammatory processes. On the other hand, activated neutrophils are cells of the first line of immune defense that are able to release extracellular traps (NETs). NETs are formed of DNA and granular components; however, the excessive release of NETs is associated with the development of autoimmune and chronic inflammatory diseases. In this study, we identified that conditioned medium (CM) from hAMSC was able to diminish NETs release, as well as the production of reactive oxygen species (ROS) and the mitochondrial membrane potential from LPS-stimulated mouse bone marrow-derived neutrophils (BMN). Interestingly, NETs inhibition, ROS levels decrease and mitochondrial membrane potential loss were reverted when LPS-stimulated murine derived BMN were exposed to the CM from hAMSC transfected with TSG-6-siRNA. Finally, rhTSG6 was able to significantly diminish NETs release in BMN. These data suggest an inhibition mechanism of NETs ROS-dependent in which TSG-6 participates. Consequently, we propose the hAMSC use as a therapeutic candidate in the treatment of inflammatory diseases in which NETs are involved.

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Section: Resultsmentioning

confidence: 99%

Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6

Magaña‐Guerrero¹,

Domínguez-López²,

Martinez-Aboytes³

et al. 2017

Sci Rep

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“…Moreover, enhanced levels of circulating FFA and triacylglycerols cause insulin resistance and also neutrophilic inflammation (53, 54). Neutrophils from streptozotocin-induced diabetic rats exhibit defective autophagy, depolarized mitochondrial potential, and low ATP levels (116). Homocysteine, a sulfur-containing amino acid, levels increased significantly during diabetes and also induced NETosis (134).…”

Section: Metabolic Adaptations In Neutrophils During Pathological Conmentioning

confidence: 99%

Metabolic Insight of Neutrophils in Health and Disease

2019

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Neutrophils are the most abundant, short lived, and terminally differentiated leukocytes with distinct tiers of arsenals to counter pathogens. Neutrophils were traditionally considered transcriptionally inactive cells, but recent researches in the field led to a paradigm shift in neutrophil biology and revealed subpopulation heterogeneity, and functions pivotal to immunity and inflammation. Furthermore, recent unfolding of metabolic plasticity in neutrophils has challenged the long-standing concept of their sole dependence on glycolytic pathway. Metabolic adaptations and distinct regulations have been identified which are critical for neutrophil differentiation and functions. The metabolic reprogramming of neutrophils by inflammatory mediators or during pathologies such as sepsis, diabetes, glucose-6-phosphate dehydrogenase deficiency, glycogen storage diseases (GSDs), systemic lupus erythematosus (SLE), rheumatoid arthritis, and cancer are now being explored. In this review, we discuss recent developments in understanding of the metabolic regulation, that may provide clues for better management and newer therapeutic opportunities for neutrophil centric immuno-deficiencies and inflammatory disorders.

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“…In addition to chemotaxis, other neutrophil functions are also altered in diabetes, such as phagocytosis, bactericidal activity, and ROS production, which contribute to the high incidence and severity of infections in diabetic patients ( 48 ). Thus, we explored whether glucagon could impact ROS generation by neutrophils in vitro and observed that it inhibited zymosan A-induced ROS production by murine neutrophils in vitro .…”

Section: Discussionmentioning

confidence: 99%

Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice

Insuela

Ferrero

Gonçalves-de-Albuquerque

et al. 2021

Front. Immunol.

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Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.

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Autophagy Is Impaired in Neutrophils from Streptozotocin-Induced Diabetic Rats

Cited by 15 publications

References 72 publications

Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6

Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6

Metabolic Insight of Neutrophils in Health and Disease

Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice

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