Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation

Hideaki Inoue, Jun Shirakawa, Yu Togashi, Kazuki Tajima, Tomoko Okuyama, Mayu Kyohara, Yui Tanaka, Kazuki Orime, Yoshifumi Saisho, Taketo Yamada, Kimitaka Shibue, Rohit N. Kulkarni, Yasuo Terauchi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives -cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.

Original languageEnglish
Pages (from-to)5934-5946
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number16
DOIs
Publication statusPublished - 2018 Jan 1

Fingerprint

Calcium-Binding Proteins
Macrophages
Islets of Langerhans
Apoptosis
Inflammation
Toll-Like Receptor 4
Palmitates
Medical problems
Peritoneal Macrophages
Type 2 Diabetes Mellitus
Monocytes
Infiltration
Cytokines
Genes
Gene Expression
Glucose
Feedback
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation. / Inoue, Hideaki; Shirakawa, Jun; Togashi, Yu; Tajima, Kazuki; Okuyama, Tomoko; Kyohara, Mayu; Tanaka, Yui; Orime, Kazuki; Saisho, Yoshifumi; Yamada, Taketo; Shibue, Kimitaka; Kulkarni, Rohit N.; Terauchi, Yasuo.

In: Journal of Biological Chemistry, Vol. 293, No. 16, 01.01.2018, p. 5934-5946.

Research output: Contribution to journalArticle

Inoue, H, Shirakawa, J, Togashi, Y, Tajima, K, Okuyama, T, Kyohara, M, Tanaka, Y, Orime, K, Saisho, Y, Yamada, T, Shibue, K, Kulkarni, RN & Terauchi, Y 2018, 'Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation', Journal of Biological Chemistry, vol. 293, no. 16, pp. 5934-5946. https://doi.org/10.1074/jbc.M117.809228
Inoue, Hideaki ; Shirakawa, Jun ; Togashi, Yu ; Tajima, Kazuki ; Okuyama, Tomoko ; Kyohara, Mayu ; Tanaka, Yui ; Orime, Kazuki ; Saisho, Yoshifumi ; Yamada, Taketo ; Shibue, Kimitaka ; Kulkarni, Rohit N. ; Terauchi, Yasuo. / Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 16. pp. 5934-5946.
@article{9fc4263df63c47f8b33bdb64b58b7986,
title = "Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation",
abstract = "Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives -cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.",
author = "Hideaki Inoue and Jun Shirakawa and Yu Togashi and Kazuki Tajima and Tomoko Okuyama and Mayu Kyohara and Yui Tanaka and Kazuki Orime and Yoshifumi Saisho and Taketo Yamada and Kimitaka Shibue and Kulkarni, {Rohit N.} and Yasuo Terauchi",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.M117.809228",
language = "English",
volume = "293",
pages = "5934--5946",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "16",

}

TY - JOUR

T1 - Signaling between pancreatic cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation

AU - Inoue, Hideaki

AU - Shirakawa, Jun

AU - Togashi, Yu

AU - Tajima, Kazuki

AU - Okuyama, Tomoko

AU - Kyohara, Mayu

AU - Tanaka, Yui

AU - Orime, Kazuki

AU - Saisho, Yoshifumi

AU - Yamada, Taketo

AU - Shibue, Kimitaka

AU - Kulkarni, Rohit N.

AU - Terauchi, Yasuo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives -cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.

AB - Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives -cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.

UR - http://www.scopus.com/inward/record.url?scp=85045830434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045830434&partnerID=8YFLogxK

U2 - 10.1074/jbc.M117.809228

DO - 10.1074/jbc.M117.809228

M3 - Article

C2 - 29496993

AN - SCOPUS:85045830434

VL - 293

SP - 5934

EP - 5946

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 16

ER -