AMPK Amplifies IL2–STAT5 Signaling to Maintain Stability of Regulatory T Cells in Aged Mice

Abstract

AMP-activated protein kinase (AMPK), an important regulator of the aging process, is expressed in various immune cells. However, its role in regulatory T cell (Treg) stability during aging is poorly understood. Here, we addressed the role of AMPK in Treg function and stability during aging by generating Treg-specific AMPKα1 knockout mice. In this study, we found that AMPKα1-deficient Tregs failed to control inflammation as effectively as normal Tregs did during aging. AMPK knockout from Tregs reduces STAT5 phosphorylation in response to interleukin (IL)-2 stimulation, thereby destabilizing Tregs by decreasing CD25 expression. Thus, our study addressed the role of AMPK in Tregs in sensing IL-2 signaling to amplify STAT5 phosphorylation, which, in turn, supports Treg stability by maintaining CD25 expression and controlling inflamm-aging.

Probiotic-Fermented Camel Milk Attenuates Neurodegenerative Symptoms via SOX5/miR-218 Axis Orchestration in Mouse Models

“…Therefore, PBTs showed a promising and effective therapeutic approach for neurological diseases [ 58 ] due to their wide range of healthful benefits, including immunomodulatory effects, gastrointestinal barrier protection, antimicrobial activity and increased mucoadhesion compared to immunosuppressive drugs [ 59 , 60 , 61 ]. From this study, BEY treatment could be a potential therapeutic approach for neurodegenerative diseases, as has been seen in similar PBT studies previously [ 61 , 62 ].…”

Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function

“…At least a portion of this increased proliferation may be secondary to a heightened ability of cells to respond to IL2, as suggested by our data on increased CD25 expression. Reassuringly, other models have noted a similar link between AMPK and upregulation of CD25-mediated IL2 signaling ( 59 ). Notably, despite increased in vitro expansion, there was no evidence of impending exhaustion in AMPKγ2-transduced cells as measured by PD1, TIM3, and LAG3 expression and no impairment in upregulation of these markers upon further TCR stimulation.…”

AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer

“…Extrinsic AMPK activation by metformin preferentially induces Tregs ( Michalek et al ., 2011 ), and LKB1, an AMPK activator, maintains the mitochondrial fitness of Tregs ( He et al ., 2017 ). AMPK also contributes to Tregs stability ( Pokhrel et al ., 2022 ). Collectively, the balance between AMPK and mTOR orchestrates T cell transition into distinct subsets Th1, Th2, Th17, and Tregs and status (naïve, effector, and memory cells) by satisfying the metabolic requirements for each setting, implying that AMPK targeting may induce specific T cells to combat specific diseases.…”

“…Aging is a multifactorial process in which the metabolic pathways are drastically altered. As a metabolic sensor, AMPK exerts antiaging effects ( Stancu, 2015 ; Ge et al ., 2022 ; Pokhrel et al ., 2022 ). Inflammation is a hallmark of aging that increases the levels of pro-inflammatory markers in the body.…”

“…3 ). This enhances the expression of IL-2 receptor α chain to amplify the stability and functions of Tregs, consequently repressing inflammaging ( Pokhrel et al ., 2022 ). Aging also elevates nuclear factor-kappa B (NF-κB) signaling, a key pathway in inflammation ( Salminen and Kaarniranta, 2009 ; Tilstra et al ., 2011 ).…”