TY - JOUR
T1 - Fatty acid binding protein 4 promotes autoimmune diabetes by recruitment and activation of pancreatic islet macrophages
AU - Xiao, Yang
AU - Shu, Lingling
AU - Wu, Xiaoping
AU - Liu, Yang
AU - Cheong, Lai Yee
AU - Liao, Boya
AU - Xiao, Xiaoyu
AU - Hoo, Ruby L.C.
AU - Zhou, Zhiguang
AU - Xu, Aimin
N1 - Funding information:
This work is supported by grants from National Key Research and Development Program of China (2016YFC1305000, 2016YFC1305003), RGC/NSFC joint research scheme (N-HKU726/14), Hong Kong Research grant council General Research Fund (17128115), Science and Technology Major Project of Hunan Province (2017SK1020), National Natural Science Foundation of China (81700749, 81870577),National Science Foundation of Hunan Province for Excellent Young Scholars (2020JJ3056), and Sun Yat-sen University Hundred Talents Program (PT19200101).
Publisher copyright:
© 2021, Xiao et al.
PY - 2021/4/8
Y1 - 2021/4/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104160308&doi=10.1172%2fjci.insight.141814&partnerID=40&md5=bd3961a9ca8e5ed4f3748236fb5c8214
U2 - 10.1172/jci.insight.141814
DO - 10.1172/jci.insight.141814
M3 - Journal article
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 7
M1 - e141814
ER -