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01.08.2014 | Article

TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6

verfasst von: Dominika Nackiewicz, Meixia Dan, Wei He, Rosa Kim, Anisa Salmi, Sabine Rütti, Clara Westwell-Roper, Amanda Cunningham, Madeleine Speck, Carole Schuster-Klein, Beatrice Guardiola, Kathrin Maedler, Jan A. Ehses

Erschienen in: Diabetologia | Ausgabe 8/2014

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Abstract

Aims/hypothesis

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/interpretation

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.

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Titel: TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6
verfasst von: Dominika Nackiewicz
Meixia Dan
Wei He
Rosa Kim
Anisa Salmi
Sabine Rütti
Clara Westwell-Roper
Amanda Cunningham
Madeleine Speck
Carole Schuster-Klein
Beatrice Guardiola
Kathrin Maedler
Jan A. Ehses
Publikationsdatum: 01.08.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 8/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3249-1

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