Fatty acid binding protein 4 promotes autoimmune diabetes by recruitment and activation of pancreatic islet macrophages
Yang Xiao, Lingling Shu, Xiaoping Wu, Yang Liu, Lai Yee Cheong, Boya Liao, Xiaoyu Xiao, Ruby L.C. Hoo, Zhiguang Zhou, Aimin Xu
Yang Xiao, Lingling Shu, Xiaoping Wu, Yang Liu, Lai Yee Cheong, Boya Liao, Xiaoyu Xiao, Ruby L.C. Hoo, Zhiguang Zhou, Aimin Xu
View: Text | PDF
Research Article Endocrinology

Fatty acid binding protein 4 promotes autoimmune diabetes by recruitment and activation of pancreatic islet macrophages

Abstract

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.

Authors

Yang Xiao, Lingling Shu, Xiaoping Wu, Yang Liu, Lai Yee Cheong, Boya Liao, Xiaoyu Xiao, Ruby L.C. Hoo, Zhiguang Zhou, Aimin Xu

×

Figure 6

Macrophage-expressed FABP4 contributes to the development of insulitis and diabetes in NOD mice.

Options: View larger image (or click on image) Download as PowerPoint
Macrophage-expressed FABP4 contributes to the development of insulitis a...
Two-week-old female FABP4+/+NOD mice and FABP4–/–NOD mice were intravenously injected with GdCl3 (1 mg/kg) or saline every 3 days (i.v.) for 6 weeks. Diabetes incidence was monitored in the following 30 weeks. (A) Infiltration and (B) quantification of F4/80+ macrophages among CD45+ cells in islets of NOD mice treated with GdCl3 or vehicle for 6 weeks (n = 5). (C) Diabetes incidence in FABP4+/+NOD mice and FABP4–/–NOD mice treated with GdCl3 or vehicle. Diabetes incidence was diagrammed with the Kaplan-Meier method, and incidences between different groups were compared with the log-rank test (n = 18 in each group). (D) Glucose tolerance test of 14-week-old FABP4+/+NOD and FABP4–/–NOD mice treated with GdCl3 and vehicle control. (E) The quantification of area under curve of different groups (n = 5). (F) Insulitis scores determined by histological evaluation of pancreatic sections as in Figure 4B (n = 6). (G) Quantification of TUNEL-positive β cells in islets of 10-week-old FABP4+/+NOD mice and FABP4–/–NOD mice (n = 5). (H) Cleaved caspase-3 activity in pancreatic lysate of FABP4+/+NOD mice and FABP4–/–NOD mice treated with GdCl3 or vehicle for 6 weeks measured by Caspase-3 Fluorometric Assay Kit (BioVision, Inc.) (n = 5). (I) Quantification of the absolute number of CD8+ T cells in total T cells (CD3+) from islets of above mice (n = 5). (J) Quantification of the absolute numbers of Th1 (IFN-γ+CD4+), Th2 (IL-4+CD4+), Th17 (IL-17+CD4+), and Treg (Foxp3+CD4+) cells in total helper T cells (CD4+CD3+) from islets of above mice (n = 5). (K) The relative mRNA abundance of inflammatory cytokines (IFNγ, TNFα, IL1β, and MCP1) in macrophages sorted from the pancreases of above mice treated with GdCl3 or vehicle (n = 6). Data are expressed as mean ± standard deviation. Statistical significance was determined by 1-way analysis of variance or Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.