A tímusz öregedésének molekuláris mechanizmusa: új intervenciós célpont azonosítása

Abstract

The PPAR (peroxisome proliferator-activated receptor) molecular family is widely studied (1-3). These nuclear receptor proteins possess transcription factor activities and influence multiple cellular events at the molecular level including adipocyte differentiation and metabolism. Among them, PPARgamma is of particular interest being expressed by all adipose tissue subtypes and being indispensable for adipose tissue development and for the homeostasis of physiological metabolism (4-7). As a consequence, in the mouse systemic loss of PPARgamma activity severely impairs glucose and lipid metabolism as characterized by others (8-10). In accordance, PPARgamma null mice are only viable if using conditional knockout strategy (11). Similar to the mouse above, in human PPARgamma haplo-insufficiency leads to the development of a rare metabolic condition known as familial partial lipodystrophy, type 3 (FPLD3, ORPHA 79083) also characterized by diabetes and dyslipidemia (12-15). In mammals systemic PPARgamma activity may be increased at multiple levels. Environmental factors including excessive caloric consumption or corticosteroid exposure increase PPARgamma activity systemically (16-18). Pharmacological systemic activation may be achieved through administration of thiazolidinediones (TZDs) previously used as part of oral anti-diabetic treatment, but currently neglected due to adverse cardiovascular side-effects (19, 20). Genetic engineering-based enhancement of PPARgamma activity in mouse models has also been performed (21). In every case increased PPARgamma activity promotes adipose tissue development at multiple sites of the body. Thymic aging is observed as adipose involution during which the functional thymus niche that normally supports T-cell production is gradually lost and replaced by adipose tissue (22). The process starts focally in childhood then spreads and accelerates with puberty due to hormonal changes (23). Diminishing T-cell production results in decreased availability of fresh naïve T-cells (24). Consequences include increasing incidence of infection, cancer and autoimmunity observed at senior ages (25, 26). Thymic adipose involution appears to be PPARgamma-dependent: any condition that systemically enhances PPARgamma activity – either environmental, pharmacological or genetic – accelerates thymic senescence or adipose involution with all its immunological consequences (27-32). However, the opposite phenomenon whether systemically decreased PPARgamma activity can ameliorate long-term functional immune parameters has barely been addressed (33, 34). For this reason we have set out to characterize the effect of systemic genetic PPARgamma loss of function on long-term immune homeostasis in both mouse and human.