Abstract
Neutrophils are abundant, short-lived leukocytes that play a key role in the immune defense against microbial infections. These cells die by apoptosis following activation and uptake of microbes and will also enter apoptosis spontaneously at the end of their lifespan if they do not encounter a pathogen. Adiponectin exerts anti-inflammatory effects on neutrophil antimicrobial functions, but whether this abundant adipokine influences neutrophil apoptosis is unknown. Here we report that adiponectin in the physiological range (1–10 μg/ml) reduced apoptosis in resting neutrophils, decreasing caspase-3 cleavage and maintaining Mcl-1 expression by stabilizing this anti-apoptotic protein. We show that adiponectin induced phosphorylation of AMP-activated kinase (AMPK), protein kinase B (PKB), extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen activated protein kinase (MAPK). Pharmacological inhibition of AMPK, PKB and ERK 1/2 ablated the pro-survival effects of adiponectin and treatment of neutrophils with an AMPK specific activator (AICAR) and AMPK inhibitor (compound C) respectively decreased and increased apoptosis. Finally, activation of AMPK by AICAR or adiponectin also decreased ceramide accumulation in the neutrophil cell membrane, a process involved in the early stages of spontaneous apoptosis, giving another possible mechanism downstream of AMPK activation for the inhibition of neutrophil apoptosis.
Highlights
Neutrophils, the most numerous immune cells in the circulation, represent the first line of protection against microbial and fungal infection
In this study we show that adiponectin delayed apoptosis of human neutrophils by activating AMPK, protein kinase B (PKB), ERK 1/2, revealing for the first time that signalling through AMPK enhances neutrophil lifespan and is required for adiponectin’s antiapoptotic effect
We found that addition of adiponectin in the physiological range (1–10 lg/ml [29, 30]) reduced neutrophil apoptosis in a dose dependent manner after both 6 and 20 h incubation (Fig. 1a, b)
Summary
Neutrophils, the most numerous immune cells in the circulation, represent the first line of protection against microbial and fungal infection These post mitotic cells are characterised by a very short lifespan, undergoing constitutive apoptosis within 5 days after leaving the bone marrow [1]. The activation of the MAPK ERK 1/2 and the PI3K/PKB axis following treatment of cells with LPS [13], TLR agonists [14] and granulocyte macrophage colony-stimulating factor (GM-CSF) [15], results in the maintenance of Mcl-1 Both ERK 1/2 and PI3K/PKB have been found to increase Mcl-1 protein levels mainly by stabilizing the protein through specific phosphorylations which delay Mcl-1 degradation and increase its half-life [16]
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