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 Lc Hoo, Zhiguang Zhou, Aimin Xu
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 7 (04 08 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 33690220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Benzothiazoles
• Carbocyanines
• FABP4 protein, human
• Fabp4 protein, mouse
• Fatty Acid-Binding Proteins
• 3,3'-dipropyl-2,2'-thiadicarbocyanine

Topics

• Adult
• Animals
• Autoantibodies (blood)
• Benzothiazoles
• Bone Marrow Transplantation
• Carbocyanines
• Diabetes Mellitus, Experimental (immunology, therapy)
• Diabetes Mellitus, Type 1 (immunology, metabolism, pathology, therapy)
• Fatty Acid-Binding Proteins (blood, genetics, immunology, metabolism)
• Female
• Humans
• Islets of Langerhans (immunology, pathology)
• Macrophages (immunology, pathology)
• Male
• Mice, Inbred NOD
• Mice, Mutant Strains
• Middle Aged
• T-Lymphocytes (immunology)
• Mice