br Role of AMPK in inflammation

Role of AMPK in inflammation signaling Pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), activate Ikβ kinase (IKKβ), which phosphorylates IκBα, triggering the degradation of proteasomal IκB. This liberates active nuclear factor kB (NF-kB) to translocate into the nucleus and promote inflammatory target gene expression in a positive feedback loop that leads to a further increase in inflammation. Interestingly, several studies have demonstrated that AMPK indirectly inhibits NF-kB activation through multiple downstream pathways that suppress the expression of inflammatory genes, including the activation of sirtuin 1 (SIRT1), FOXO and PGC1α (Jeon, 2016) (Fig. 3). SIRT1 is a class of NAD+ dependent histone deacetylases that regulates critical physiological processes, including glucose/lipid metabolism, fatty Letermovir oxidation, autophagy/apoptosis and senescence, through its deacetylase action on many signaling proteins and histones, promoting chromatin condensation and thereby silencing gene transcription (Chung et al., 2010, Xie et al., 2013). SIRT1 has a crosstalk with AMPK in the regulation of oxidative metabolism and inflammation. SIRT1 promotes the deacetylation of LKB1, which consequently triggers AMPK activation. In turn, AMPK increases cellular NAD+ levels, inducing the activation of SIRT1, which directly inhibits NF-κB signaling through the deacetylation of p65 (Chung et al., 2010, Salminen et al., 2008, Xie et al., 2013). AMPK/p53/NF-κB and AMPK/FoxO/NF-κB signaling are other possible anti-inflammatory pathways. Both p-53 and FoxO are transcription factors involved in the regulation of energy metabolism, cell growth and inflammation (Peng, 2008, Salminen and Kaarniranta, 2011). AMPK can activate the function of these factors through direct phosphorylation, which consequently inhibits NF-κB signaling (Greer et al., 2007, Maclaine and Hupp, 2009, Salminen and Kaarniranta, 2011). AMPK also modulates the NF-kB pathway by phosphorylating eNOS at Ser1177, which contributes an increase in NO production. A positive feedback loop between AMPK and eNOS has also been described, in which the phosphorylation of eNOS implies the activation of AMPK (Ewart and Kennedy, 2011, Hattori et al., 2008, Zhang et al., 2006). Activated pro-inflammatory immune cells mainly generate energy through glycolysis, whereas anti-inflammatory immune cells predominantly generate energy through oxidative phosphorylation. AMPK is critical to the switch between oxidative versus glycolytic metabolism and has therefore been implicated in regulating metabolic processes that direct immune function. AMPK/LKB1 acts as a key metabolic control in activated T cells by suppressing nutrient uptake, energy production (glycolysis) and biosynthesis (mTOR), which may regulate the transition from CD8+ T effector cells to CD8+ T memory cells as well as from CD4+ T effector cells (Th1, Th2, and Th17) to CD4+ regulatory T cells. Moreover, the silencing of LKB1 or AMPK expression promotes the development of pro-inflammatory Th cells (see review in Blagih et al., 2012). One possible mechanism involved in this transition from glycolytic to mitochondrial metabolism is the inhibition of mTORC1 by AMPK, which attenuates the hypoxia-inducible factor 1 (HIF-1)-mediated transcription of glycolytic genes, promoting oxidative metabolism (Fullerton and Steinberg, 2013) (Fig. 2). There is evidence that AMPK regulates the metabolic processes that direct immune function in macrophages, T cells and dendritic cells. Interesting studies using RNAi or adenovirus expressing dominant negative and constitutively active AMPKα1 have demonstrated that AMPK activation prevents the lipopolysaccharide (LPS)-induced and fatty acid-induced production of inflammatory cytokines. Galic et al. (2011) found that the genetic deletion of AMPKβ1 reduced macrophage AMPK activity, ACC phosphorylation and mitochondrial enzyme content, resulting in increased macrophage lipid accumulation and inflammation. Similarly, the adoptive transfer of β1−/− bone marrow into wild type (WT) recipient mice resulted in the activation of adipose tissue macrophages, leading to systemic inflammation, hyperinsulinemia and hyperglycemia. These studies demonstrate that AMPK is crucial to suppressing lipid-induced inflammation and the development of obesity-induced insulin resistance.