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

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing beta 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 beta 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.

Automated summary

The study reveals that elevated levels of FABP4 in patients with type 1 diabetes and their relatives are positively correlated with several islet autoantibodies. Inhibiting FABP4 expression can reduce the development of autoimmune diabetes in NOD mice, suggesting FABP4 plays a crucial role in activating innate and adaptive immune responses in islets.