, Volume 57, Issue 8, pp 1645–1654 | Cite as

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

  • 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



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.


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.


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.


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.


Beta cell Diabetes Inflammation Pancreatic islet Toll-like receptor 2 Toll-like receptor 4 



Bone-marrow-derived macrophage


Chemokine (C-C motif) ligand 2


Danger-associated molecular patterns


Glucose-stimulated insulin secretion




Pathogen-associated molecular patterns


Quantitative PCR


Toll-like receptor





We thank L. Xu and M. Komba for technical assistance provided by the CFRI FACS core and islet isolation core facilities, respectively.


This work was supported by funding from the Child and Family Research Institute (JAE), the University of British Columbia (JAE), the Canadian Institutes of Health Research (PCN-110793 and PNI-120292; JAE), the European Research Council (KM), the Diabetes Competence Network KKNDm supported by the Federal Ministry of Germany (BMBF; KM), and a collaborative research agreement with Servier (JAE, KM). JAE has salary support from a Child and Family Research Institute Investigator Award and a Canadian Diabetes Association scholar award. DN is supported by a UBC Transplantation Training Program and a CIHR-Vanier Canada Graduate Scholarship. CW-R is supported by a CIHR-Vanier Canada Graduate Scholarship.

Duality of interest

CS-K and BG are employees of Servier, France. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Contribution statement

DN, MD, WH, RK, AS, SR, CW-R, AC, MS designed and performed experiments, and analysed data. KM designed experiments and CS-K and BG contributed to the conception and design of the study. All authors edited the manuscript and approved the final version. JAE supervised the study, designed and performed experiments, analysed data and wrote the manuscript. JAE is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Dominika Nackiewicz
    • 1
  • Meixia Dan
    • 1
  • Wei He
    • 2
  • Rosa Kim
    • 1
  • Anisa Salmi
    • 1
  • Sabine Rütti
    • 3
  • Clara Westwell-Roper
    • 4
  • Amanda Cunningham
    • 1
  • Madeleine Speck
    • 1
  • Carole Schuster-Klein
    • 5
  • Beatrice Guardiola
    • 5
  • Kathrin Maedler
    • 2
  • Jan A. Ehses
    • 1
    • 6
  1. 1.Department of Surgery, Faculty of MedicineThe University of British Columbia, Child and Family Research InstituteVancouverCanada
  2. 2.Center for Biomolecular InteractionsThe University of BremenBremenGermany
  3. 3.Department of Genetic Medicine and Development, University Medical CenterUniversity of GenevaGenevaSwitzerland
  4. 4.Department of Pathology and Laboratory Medicine, Faculty of MedicineThe University of British Columbia, Child and Family Research InstituteVancouverCanada
  5. 5.ADIR – Groupe de Recherche ServierSuresnesFrance
  6. 6.Department of Cellular and Physiological Sciences, Faculty of MedicineThe University of British Columbia, Child and Family Research InstituteVancouverCanada

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