TY  - JOUR
A1  - Martin, Lisa Maria
A1  - Möller, Moritz
A1  - Weiß, Ulrike
A1  - Russe, Otto
A1  - Scholich, Klaus
A1  - Pierre, Sandra
A1  - Geisslinger, Gerd
A1  - Niederberger, Ellen
T1  - 5-Amino-1-β-D-Ribofuranosyl-Imidazole-4-Carboxamide (AICAR) reduces peripheral inflammation by macrophage phenotype shift
T2  - International journal of molecular sciences
N2  - 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.
KW  - AMPK
KW  - AICAR
KW  - metformin
KW  - inflammation
KW  - macrophage
KW  - cytokines
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51223
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-512239
SN  - 1661-6596
SN  - 1422-0067
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 20
IS  - 13, Art. 3255
SP  - 1
EP  - 16
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -