AMP‐activated protein kinase enhances the phagocytic ability of macrophages and neutrophils

Abstract

Although AMPK plays well-established roles in the modulation of energy balance, recent studies have shown that AMPK activation has potent anti-inflammatory effects. In the present experiments, we examined the role of AMPK in phagocytosis. We found that ingestion of Escherichia coli or apoptotic cells by macrophages increased AMPK activity. AMPK activation increased the ability of neutrophils or macrophages to ingest bacteria (by 46 ± 7.8 or 85 ± 26%, respectively, compared to control, P<0.05) and the ability of macrophages to ingest apoptotic cells (by 21 ± 1.4%, P<0.05 compared to control). AMPK activation resulted in cytoskeletal reorganization, including enhanced formation of actin and microtubule networks. Activation of PAK1/2 and WAVE2, which are downstream effectors of Rac1, accompanied AMPK activation. AMPK activation also induced phosphorylation of CLIP-170, a protein that participates in microtubule synthesis. The increase in phagocytosis was reversible by the specific AMPK inhibitor compound C, siRNA to AMPKα1, Rac1 inhibitors, or agents that disrupt actin or microtubule networks. In vivo, AMPK activation resulted in enhanced phagocytosis of bacteria in the lungs by 75 ± 5% vs. control (P<0.05). These results demonstrate a novel function for AMPK in enhancing the phagocytic activity of neutrophils and macrophages.

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

“…For example, AMPK activation was associated with enhanced T cell chemotaxis or migration of epithelial cells (38,50). AMPK activation has also been shown to enhance the phagocytic ability of macrophages, including uptake of bacteria, synthetic beads or apoptotic cells (39). These results are consistent with an ability of activated AMPK to facilitate microbial eradication through mechanisms that involve enhancement of neutrophil chemotaxis and/or bacterial uptake.…”

“…Recent studies, including results obtained from our laboratory (39), have shown that metformin or other AMPK activators enhance cell mobility and also phagocytosis. For example, AMPK activation was associated with enhanced T cell chemotaxis or migration of epithelial cells (38,50).…”

“…Recent studies have shown that activated AMPK can also modulate the resolution of inflammatory conditions due to enhancement of the phagocytic ability of macrophages and neutrophils. In particular, AMPK activation increased the uptake of bacteria and enhanced efferocytosis, an essential process in the resolution of inflammation in which apoptotic cells are ingested and cleared by phagocytic cells (39,59,60). Beneficial effects of AMPK activation also were related to improvement of vascular integrity in mice models for endotoxemia-induced ALI and to airway remodeling in asthma (34,61).…”

“…Phagocytosis of fluorescent labeled E. coli or S. aureus by neutrophils was performed as described previously (39). In brief, phagocytosis of fluorescently labeled bacteria by neutrophils pretreated with or without metformin (500 μmol/L, 2.5 h) was determined by adding tenfold excess of E. coli or S. aureus to the cells.…”

“…In addition, metformin enhances host defense mechanisms by facilitating the chemotaxis and maturation of T cells (37,38). Besides its antiinflammatory actions, activated AMPK was recently shown to increase the phagocytic ability of macrophages (39). Although these studies revealed a beneficial effect of metformin in acute inflammatory conditions, there is little information concerning the ability of metformin or other AMPK activators to alter primary innate immune responses, and particularly bacterial eradication.…”