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.

Highlights

  • Type 1 diabetes is an organ-specific autoimmune disease caused by the selective destruction of insulin-producing β cells located in pancreatic islets of Langerhans [1]

  • Our results identify augmented fatty acid binding protein 4 (FABP4) expression in islet macrophages as an important mediator triggering the onset of β cell autoimmunity by enhancing inflammatory milieu in the islets, suggesting that pharmacological inhibition of FABP4 might be an effective approach for early therapeutic intervention of autoimmune diabetes

  • These associations remained significant after adjustment for age and BMI, suggesting that elevated FABP4 may be causally involved in autoimmune destruction of β cells in patients with type 1 diabetes

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Summary

Introduction

Type 1 diabetes is an organ-specific autoimmune disease caused by the selective destruction of insulin-producing β cells located in pancreatic islets of Langerhans [1]. Similar to other autoimmune disorders, type 1 diabetes is a chronic inflammatory disease involving dysfunction of both innate and adaptive immunity. Infiltration and activation of several types of innate immune cells in the islets, including macrophages, neutrophils, natural killer (NK) cells, and dendritic cells (DCs), occur at the initial stage of type 1 diabetes and are the major contributor to the establishment of inflammatory milieu in the islets, which is prerequisite for subsequent β cell death and augmentation of the adaptive immune effector response of islet-specific autoreactive CD4+ T cells and cytotoxic CD8+ T cells [2, 3]. Macrophages are the major population of infiltrated immunocytes at the early stage of insulitis in NOD mice and diabetes-prone BB rats [5, 6] and are found in the islets of patients with recent-onset type 1 diabetic patients [7]. The etiologic factors triggering the recruitment and activation of islet macrophages in the early pathogenesis of type 1 diabetes remain obscure

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