Signaling between pancreatic β 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 β 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 β-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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 16 Pg. 5934-5946 (04 20 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29496993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Calgranulin A
• Palmitates
• Toll-Like Receptor 4
• Glucose

Topics

• Animals
• Apoptosis
• Calgranulin A (immunology)
• Cell Line
• Cells, Cultured
• Glucose (immunology)
• Humans
• Inflammation (immunology)
• Insulin-Secreting Cells (cytology, immunology)
• Macrophages (cytology, immunology)
• Male
• Mice, Inbred C57BL
• Palmitates (immunology)
• Signal Transduction
• Toll-Like Receptor 4 (immunology)