| Autor: |
Xiao Y; National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China., Shu L; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Hematologic Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Medicine, and., Wu X; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China., Liu Y; Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China., Cheong LY; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Medicine, and., Liao B; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China., Xiao X; National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China., Hoo RL; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China., Zhou Z; National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China., Xu A; State Key Laboratory of Pharmaceutical Biotechnology.; Department of Medicine, and.; Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China. |
| Abstrakt: |
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. |
