Abstract
The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.
Highlights
The AMP-activated kinase (AMPK) is a heterotrimeric protein consisting of two regulatory (β and γ) and one catalytic (α) subunits which all exist in at least two isoforms
The results showed a significant increase in p-AMPK in the paw tissue of AICAR-treated mice, indicating kinase activation (Figure 1C)
Previous data from our group indicated that the activation of AMPK by AICAR leads to reduced inflammatory hyperalgesia which is associated with potent local antiinflammatory effects in the zymosan-induced paw inflammation model
Summary
The AMP-activated kinase (AMPK) is a heterotrimeric protein consisting of two regulatory (β and γ) and one catalytic (α) subunits which all exist in at least two isoforms. Its activation has been associated with the induction of catabolic, energy producing processes such as glucose uptake and fatty acid oxidation [2,3,4,5,6,7], the regulation of appetite, and antiinflammatory [8,9] and antinociceptive effects [10,11]. It has been discussed as a useful tool for the treatment of obesity and diabetes [1,12,13], as well as inflammatory diseases and pain [10,11]. The potential phenotype switch was investigated in mouse macrophages after stimulation with proinflammatory lipopolysaccharide (LPS) and antiinflammatory IL-4—with and without addition of the AMPK activators AICAR and metformin
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