Insulin Modulates the Inflammatory Granulocyte Response to Streptococci via Phosphatidylinositol 3-Kinase

Kenzel, Sybille; Mergen, Miriam; Süßkind-Schwendi, Julius von; Wennekamp, Julia; Deshmukh, S. D.; Haeffner, Monika; Triantafyllopoulou, Antigoni; Fuchs, Sebastian; Farmand, Susan; Santos-Sierra, Sandra; Seufert, Jochen; Berg, Timo K. van den; Kuijpers, Taco W.; Henneke, Philipp

doi:10.4049/jimmunol.1200205

Cited by 9 publications

(7 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50 PI3K/AKT inhibition alters host inflammatory and innate immune responses, increases infection risk in different organ systems, and decreases survival. 48, 49, 51–53 Wortmannin inhibition of PI3K/AKT increases morbidity and mortality following experimental endotoxemia and polymicrobial sepsis. 48, 49 Clinically, patients receiving treatment with PI3K/AKT/mTOR inhibitors have increased infection risk – with the urinary tract being the most likely site of infection.…”

Section: Discussionmentioning

confidence: 99%

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Eichler

Becknell

Easterling

et al. 2016

Kidney International

View full text Add to dashboard Cite

Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations.

show abstract

Section: Discussionmentioning

confidence: 99%

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Eichler

Becknell

Easterling

et al. 2016

Kidney International

View full text Add to dashboard Cite

show abstract

“…It is possible that cats require this same dose. It is also possible that the initial dose of 2.2 U/kg/240 mL bag of 0.9% NaCl resulted in a better outcome because other properties of insulin, such as its anti‐inflammatory effect, improved the outcome at the higher dose …”

Section: Discussionmentioning

confidence: 99%

Retrospective evaluation of risk factors and outcome predictors in cats with diabetic ketoacidosis (1997–2007): 93 cases

Cooper

Drobatz

Lennon

et al. 2015

J Vet Emergen Crit Care

View full text Add to dashboard Cite

show abstract

“…In vitro , PBMC from healthy neonates rapidly respond to GBS with the formation of large amounts of IL-6, TNF, IL-8, and IL-1β ( 155 – 157 ). Since insulin suppresses the cytokine formation in response to GBS, peripheral insulin resistance present in newborn infants and particularly during sepsis may promote the inflammatory process ( 158 ). Excessive stimulation of immune cells may be further enhanced by a reduction of antimicrobial phagocyte properties, which are markedly impaired in neonates and may allow for pathogen persistence and failure to contract the immune response ( 159 – 161 ).…”

Section: Gbs In (Transient) Immunodeficiencymentioning

confidence: 99%

Interaction of Streptococcus agalactiae and Cellular Innate Immunity in Colonization and Disease

Landwehr-Kenzel

Henneke

2014

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Streptococcus agalactiae (Group B streptococcus, GBS) is highly adapted to humans, where it is a normal constituent of the intestinal and vaginal flora. Yet, GBS has highly invasive potential and causes excessive inflammation, sepsis, and death at the beginning of life, in the elderly and in diabetic patients. Thus, GBS is a model pathobiont that thrives in the healthy host, but has not lost its potential virulence during coevolution with mankind. It remains incompletely understood how the innate immune system contains GBS in the natural niches, the intestinal and genital tracts, and which molecular events underlie breakdown of mucocutaneous resistance. Newborn infants between days 7 and 90 of life are at risk of a particularly striking sepsis manifestation (late-onset disease), where the transition from colonization to invasion and dissemination, and thus from health to severe sepsis is typically fulminant and not predictable. The great majority of late-onset sepsis cases are caused by one clone, GBS ST17, which expresses HvgA as a signature virulence factor and adhesin. In mice, HvgA promotes the crossing of both the mucosal and the blood–brain barrier. Expression levels of HvgA and other GBS virulence factors, such as pili and toxins, are regulated by the upstream two-component control system CovR/S. This in turn is modulated by acidic epithelial pH, high glucose levels, and during the passage through the mouse intestine. After invasion, GBS has the ability to subvert innate immunity by mechanisms like glycerinaldehyde-3-phosphate-dehydrogenase-dependent induction of IL-10 and β-protein binding to the inhibitory phagocyte receptors sialic acid binding immunoglobulin-like lectin 5 and 14. On the host side, sensing of GBS nucleic acids and lipopeptides by both Toll-like receptors and the inflammasome appears to be critical for host resistance against GBS. Yet, comprehensive models on the interplay between GBS and human immune cells at the colonizing site are just emerging.

show abstract

Insulin Modulates the Inflammatory Granulocyte Response to Streptococci via Phosphatidylinositol 3-Kinase

Cited by 9 publications

References 69 publications

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Retrospective evaluation of risk factors and outcome predictors in cats with diabetic ketoacidosis (1997–2007): 93 cases

Interaction of Streptococcus agalactiae and Cellular Innate Immunity in Colonization and Disease

Contact Info

Product

Resources

About