5-Amino-1-β-D-Ribofuranosyl-Imidazole-4-Carboxamide (AICAR) Reduces Peripheral Inflammation by Macrophage Phenotype Shift.

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.

• Authors: Lisa Maria Martin, Moritz Möller, Ulrike Weiss, Otto Quintus Russe, Klaus Scholich, Sandra Pierre, Gerd Geisslinger, Ellen Niederberger
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 13 (Jul 02 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31269729 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Ribonucleotides
• Aminoimidazole Carboxamide
• AICA ribonucleotide

Topics

• Aminoimidazole Carboxamide (analogs & derivatives, therapeutic use)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cells, Cultured
• Edema (complications, drug therapy, immunology)
• Hyperalgesia (complications, drug therapy, immunology)
• Inflammation (complications, drug therapy, immunology)
• Macrophages (drug effects, immunology)
• Male
• Mice, Inbred C57BL
• Ribonucleotides (therapeutic use)