title: Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase.
abstract: Group B streptococci (GBS; Streptococcus agalactiae) are a major cause of invasive infections in newborn infants and in patients with type 2 diabetes. Both patient groups exhibit peripheral insulin resistance and alterations in polymorphonuclear leukocyte (PML) function. In this investigation, we studied the PML response repertoire to GBS with a focus on TLR signaling and the modulation of this response by insulin in mice and humans. We found that GBS-induced, MyD88-dependent chemokine formation of PML was specifically downmodulated by insulin via insulin receptor-mediated induction of PI3K. PI3K inhibited transcription of chemokine genes on the level of NF-κB activation and binding. Insulin specifically modulated the chemokine response of PML to whole bacteria, but affected neither activation by purified TLR agonists nor antimicrobial properties, such as migration, phagocytosis, bacterial killing, and formation of reactive oxygen species. The targeted modulation of bacteria-induced chemokine formation by insulin via PI3K may form a basis for the development of novel targets of adjunctive sepsis therapy.
authors.affiliation: Center for Pediatric and Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Kenzel
authors.forename: Miriam
authors.initials: M
authors.lastname: Mergen
authors.forename: Julius
authors.initials: J
authors.lastname: von Süßkind-Schwendi
authors.forename: Julia
authors.initials: J
authors.lastname: Wennekamp
authors.forename: Sachin D
authors.initials: SD
authors.lastname: Deshmukh
authors.forename: Monika
authors.initials: M
authors.lastname: Haeffner
authors.forename: Antigoni
authors.initials: A
authors.lastname: Triantafyllopoulou
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.forename: Susan
authors.initials: S
authors.lastname: Farmand
authors.forename: Sandra
authors.initials: S
authors.lastname: Santos-Sierra
authors.forename: Jochen
authors.initials: J
authors.lastname: Seufert
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Philipp
authors.initials: P
authors.lastname: Henneke
mesh_terms: D000328:Adult; D000818:Animals; D006098:Granulocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D013292:Streptococcus agalactiae / Q000276:immunology*
chemical_list: D007328:Insulin; D058539:Phosphatidylinositol 3-Kinase