AMP activated protein kinase AMPK is a key

AMP-activated protein kinase (AMPK) is a key cellular energy sensor that maintains energy homeostasis at the cellular and whole-organism level (Hardie et al., 2012). Functionally, the AMPK pathway sustains adenosine triphosphate (ATP) production through activation of fatty gamma-Glu-Cys oxidation and autophagy in response to stress. In contrast, activation of AMPK limits ATP-consuming biosynthetic processes such as gluconeogenesis and lipid and protein synthesis. Dysfunction of AMPK signaling is implicated in various human diseases such as metabolic diseases, infectious diseases, and cancers (Carling, 2017). Recent studies have shown that AMPK activation by drugs or small molecular compounds protects against experimental sepsis in mice (Lee et al., 2017, Liu et al., 2015, Mulchandani et al., 2015, Escobar et al., 2015, Park et al., 2013), indicating that AMPK plays an important role in the pathogenesis of sepsis.
Results
Discussion Sepsis and septic shock remain challenging to intensive care units worldwide and have limited treatment options; therefore, identification of targetable key players in systemic inflammation and multiple organ failure is urgently needed (Hotchkiss et al., 2016). Here, we characterize the functional role of AMPK in the pathogenesis of sepsis. In particular, we demonstrate in mouse models that AMPKα-deficiency in myeloid cells accelerates septic death through PKM2-dependent lactate production and subsequent HMGB1 release (Fig. 7). These findings shed new light on how cellular energy sensor controls DAMP release and could have major implications for the development of strategies to target immunometabolism in sepsis as well as other lethal inflammatory diseases. The pathogenesis of sepsis is generally dependent on the activation of the innate immune response (Wiersinga et al., 2014, Srivastava and Mannam, 2015). Altering the balance between pro- and anti-inflammatory mediators derived from host cells therefore defines the progression and severity of sepsis. For example, early response proinflammatory mediators include tumor necrosis factor, interferon-γ, interleukin (IL)-1β, and IL-6. In contrast, HMGB1 is a late mediator of endotoxemia and septic shock (Wang et al., 1999, Wang et al., 2001). In addition to being engaged in bacterial infections, HMGB1 release is involved in sterile inflammation from surgery, trauma, and ischemia (Andersson and Tracey, 2011). Extracellular HMGB1 can bind various types of pathogen-associated molecular patterns (e.g., LPS) and DAMPs (e.g., DNA and histones) to amplify the inflammatory response through engagement of multiple receptors such as Toll-like receptors and advanced glycosylation end product-specific receptor (Kang et al., 2014). Many agents capable of inhibiting HMGB1 release have also been proven protective in experimental models of sepsis, but the protective mechanisms remain poorly elucidated. Our current study demonstrates that AMPK is an important regulator of HMGB1 release in activated macrophages and monocytes. We observed that genetic or pharmacologic activation of AMPK blocked HMGB1 release in macrophages (BMDMs) and monocytes (THP1) following LPS treatment or Escherichia coli infection. THP1 cells derived from human monocytic leukemia are the most widely used cell lines to investigate the function and regulation of monocytes in vitro (Chanput et al., 2014). The biological responses of primary PBMCs and the THP-1 cell line to inflammation stimulus may differ. In addition to THP1 cell lines, we also observed that AMPK activators inhibited LPS-induced cytokine release in PBMCs. Compound C has a relatively short shelf life and will degrade after a period of several weeks. Solutions of compound C are best prepared fresh. In addition to Compound C, other potential AMPK inhibitors (e.g., WZ4003 and HTH-01-015), as well as knockdown of AMPKα, promoted HMGB1 release in activated macrophages and monocytes. These findings support other research evidence that AMPK activation blocks HMGB1 release from immune cells, endothelial cells, or various inflammation animal models (Kim et al., 2015, Tsoyi et al., 2011, Chang, 2015, Vitali et al., 2015). Compound C also plays an AMPK-independent anti-inflammation role in some conditions; results should be interpreted cautiously when this compound is used as an AMPK inhibitor (Lee et al., 2016).