The Roles Of NKT Cells In Adipose Tissue Metaflammation

With the improvement of living standards,obesity has become one of the major threats to human health.Obesity can lead to insulin resistance,which result in atherosclerosis,hypertension and type 2 diabetes.In addition,obesity can cause chronic inflammation in adipose tissue,liver and pancreas.Metaflammation is named by the chronic inflammation caused by obesity.However,to date,the mechanism by which metabolic disorders trigger metaflammation remain unclear.Imbalance of immune system plays important roles in obesity-induced metaflammation.Many types of immune cells,including macrophages,NK(natural killer)cells,ILC2(type 2 innate lymphoid)cells and NKT(natural killer T)cells are involved in obesity-induced metaflammation.The function of macrophages in metaflammation is most studied,M2 macrophages have anti-inflammatory functions,and predominantly comprise the adipose tissue macrophages in lean animals.Obesity increases the percentage of M1 macrophages,which produce large amounts of Thl cytokines and promote metaflammation and insulin resistance.However,to date,the mechanism of imbalance between M1 and M2 macrophages is not clear.Different from conventional T cells,NKT cells recognize lipid antigens presented by CD1d but not MHCs.NKT cells play an important role in immune regulation,roles of NKT cells in regulating metaflammation have been reported by several labs.However,their results are controversial.The relationship between NKT cells,imbalance of M1/M2 macrophages ratio and metaflammation is not clear.We observed a cell type-specific down regulation of CD Id expression in M2 macrophages during the progression of obesity prior to the onset of inflammation in visceral adipose tissues.Reduction of CD Id expression influenced ability of M2 macrophages to present antigens,and caused change of antigen-presenting cells from M2 macrophages to M1 macrophages.We sorted M1 and M2 macrophages from adipose tissue in NCD or HFD mice,and co-cultured with NKT cells in the presence of aGalCer.Comparing to M1 macrophages,M2 macrophages induced higher level of IL4,IL13 but lower level of IFNy from iNKT cells.The above results suggest that,NKT cells activated by M1 or M2 macrophages can lead to different immune responses.Interestingly,impaired glucose tolerance tests(GTTs)were observed in Lyz2cre Cd1dfl/fl(Lyz2?/?)mice on HFD as early as 8 weeks but disappeared after 20 weeks.On the contrary,improved GTTs were observed in Cd11ccre Cd1dfl/fl(Cd11c?/?)mice on HFD after 16 and 20 weeks but not after 8 weeks.These results indicated opposite roles of NKT cells in regulating blood glucose in obese mice through interactions with distinct APCs.With CD1d conditional KO mice we further demonstrated that,activation of NKT cells by M2 macrophages inhibited metaflammation and insulin resistance by promoting Th2 responses and M2 polarization in visceral adipose tissues of obese mice,whereas activation of NKT cells by M1 macrophages exacerbated metaflammation and insulin resistance by promoting Th1 responses and inhibiting M2 polarization.In conclusion,our results suggest that M2-specific reduction of CD Id is an initiating event,which switches NKT cell mediated immune responses and disrupts the immune balance in VATs of' obese mice.