title: TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6.
abstract: OBJECTIVE
  Inflammation contributes to pancreatic beta cell dysfunction in type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in recently diagnosed type 2 diabetes patients, and TLR2- and TLR4-deficient mice are protected from the metabolic consequences of a high-fat diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated effects on islet inflammation and beta cell function.
  
  
  METHODS
  Genetic and pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 ligands on mouse islets, human islets and purified rat beta cells. Islet macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function were assessed.
  
  
  RESULTS
  Macrophages contributed to TLR2/6- and TLR4-induced islet Il1a/IL1A and Il1b/IL1B mRNA expression in mouse and human islets and IL-1β secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing Ins1, Ins2, and Pdx1 mRNA expression. Antagonism of the IL-1 receptor and neutralisation of IL-6 completely reversed the effects of activated macrophages on beta cell gene expression.
  
  
  CONCLUSIONS
  We conclude that islet macrophages are major contributors to islet IL-1β secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1β- and IL-6-mediated decreased insulin gene expression.
authors.affiliation: Department of Surgery, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nackiewicz
authors.forename: Meixia
authors.initials: M
authors.lastname: Dan
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Rosa
authors.initials: R
authors.lastname: Kim
authors.forename: Anisa
authors.initials: A
authors.lastname: Salmi
authors.forename: Sabine
authors.initials: S
authors.lastname: Rütti
authors.forename: Clara
authors.initials: C
authors.lastname: Westwell-Roper
authors.forename: Amanda
authors.initials: A
authors.lastname: Cunningham
authors.forename: Madeleine
authors.initials: M
authors.lastname: Speck
authors.forename: Carole
authors.initials: C
authors.lastname: Schuster-Klein
authors.forename: Beatrice
authors.initials: B
authors.lastname: Guardiola
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D018345:Mice, Knockout; D051381:Rats; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D007375:Interleukin-1; D015850:Interleukin-6; D051193:Toll-Like Receptors