Dendritic cells contribute to perivascular adipose tissue dysfunction in type 2 diabetes

Abstract

T2DM is a chronic disease characterized by low-grade inflammation in adipose tissue. Recent investigations have shown that a variety of immune cells can accumulate in adipose tissue contributing to the development of chronic inflammation. To date focus has been placed on specific immune cell populations including B and T lymphocytes, M1 macrophages, neutrophils, mast cells and natural killer cells. However, it remains uncertain about the exact immune cell populations in adipose tissue during T2DM. The dendritic cell is a potent antigen presenting cell that has been demonstrated to participate in the chronic inflammation associated with multiple diseases, including autoimmune disease, atherosclerosis and type 1 diabetes. Thus, it was hypothesized that dendritic cells would also play a role in the development of chronic inflammation elicited by T2DM. Firstly, our data obtained in db/db mice (T2DM murine model) provide evidence that dendritic cells do, indeed, accumulate in multiple depots of perivascular and visceral adipose tissue. Importantly, the dendritic cells target the adipose tissue rather than accumulating within the vascular wall, accompanied with increased production of pro-inflammatory factors TNF-[alpha] and IL-6 in adipose tissue. Secondly, depletion of dendritic cells within adipose tissue in db/db (db[subscript Flt3l-]/ db[subscript Flt3l-]) mice attenuated the pro-inflammatory environment. As perivascular adipose tissue exerts anti-contractile actions and potentiates vasorelaxation under physiological conditions, we examined the effects of fat from db/db mice on vascular function. The data showed that in db/db mice, both of these 'vaso-protective' effects were lost at early (6-10 weeks) and later (18-22 weeks) stages of T2DM in the presence of inflamed mesenteric adipose tissue. Depletion of dendritic cells in db[subscript Flt3l-]/ db[subscript Flt3l-]- mice greatly attenuated inflammation in perivascular adipose tissue (decreased secretion of TNF-[alpha] and IL-6) compared to the db/db and partially restored vascular function. Collectively, our studies demonstrate that the accumulation of dendritic cells in adipose tissue contributes to the pathogenesis of chronic inflammation in T2DM, resulting in impairment of anti-contractile and pro-relaxant actions of perivascular adipose tissue. Deletion of dendritic cells restores these physiological actions of adipose tissue.