Fabp4 Promotes Autoimmune Diabetes Through Activation On Macrophages And Tissue Resident Memory T Lymphocytes

Abstract

Introduction: Type 1 diabetes (T1D) is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic beta cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Our previous clinical studies demonstrated that increased circulating fatty acid binding protein 4 (FABP4), a pro-inflammatory adipokine that links obesity with its related metabolic diseases, is closely associated with beta cell autoimmunity in patients with T1D. Here we investigate the role and underlying mechanism whereby FABP4 participates in the pathogenesis of T1D. Method: FABP4+/+NOD and FABP4-/-NOD mice were generated for the study. Biochemical, immunological and in vivo imaging analysis were adopted to determine the dynamic change in the infiltration and activation of immune cells including macrophage and tissue resident memory T (Trm) cell in pancreas of FABP4+/+NOD and FABP4-/-NOD mice at different ages. Gain- and loss-of-function studies were employed to evaluate the effects of FABP4 in macrophage and Trm cell on insultitis and diabetes incidence. Flow cytometry analysis was adopted to explore the effects of FABP4 in mediating the crosstalk of immune cells. Results: A dynamic change in the expression of FABP4 was observed in macrophages and Trm cells in pancreatic islets of NOD mice at different stages. Depletion of macrophages or Trm cell in 8-week FABP4+/+NOD mice partially alleviated insulitis and reduced the development of T1D in NOD mice. However, depleting macrophages and Trm cells simultaneously delayed the onset of T1D. Flow cytometry analysis demonstrated that FABP4 deficiency significantly attenuated the polarization and infiltration of pro-inflammatory macrophages (M1) and Trm cells into pancreas, reduced the production of inflammatory cytokines, alleviated islet inflammation and beta cell damage. Conclusion: FABP4 potentiates innate immunity through enhancing the polarization of macrophages to pro-inflammatory M1 subtype in NOD mice at early stage. While at later stage FABP4 promotes the survival of Trm cell and exacerbates adaptive immunity. Thus, the inflammatory microenvironment created by FABP4 in macrophages and Trm cells enhances the release of cytotoxic molecules in pancreas, strengthening the autoimmune attack to beta cells. Acknowledgment: This research is supported by NSFC/RGC Joint Research Scheme 81461168031