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.

中文翻译：

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5-氨基-1-β-D-呋喃核糖基-咪唑-4-羧酰胺（AICAR）通过巨噬细胞表型转移减少周围炎症

5-氨基-1-β-D-呋喃呋喃糖基-咪唑-4-羧酰胺（AICAR）对AMP活化激酶（AMPK）的刺激作用与抗痛觉过敏和脊髓模型中脊髓伤害性信号传导的抑制有关。爪子发炎。减轻的伤害感受伴随着强烈的爪水肿减轻，表明周围的抗炎机制促进了伤害感受。在这项研究中，我们调查了AICAR对发炎爪子免疫细胞组成的影响，以及巨噬细胞中炎症标志物和分辨标志物的调节。通过使用荧光激活细胞分选（FACS）分析和免疫荧光，我们发现发炎的组织中可分解的M2巨噬细胞和抗炎性白介素（IL）-10的比例显着增加，而AICAR可以降低野生型小鼠的M1巨噬细胞和促炎细胞因子（如IL-1）。在AMPKα2基因敲除小鼠中，爪中巨噬细胞的M2极化缺失。该结果得到原代巨噬细胞培养物中实验的支持，该实验还显示出向前表型的转变，促炎介质的水平降低而抗炎介质的水平升高。但是，在细胞培养物中，我们未观察到AMPKα2+ / +和-/-细胞之间的差异，因此表明AICAR诱导的作用至少部分不依赖AMPK。总之，我们的结果表明，AICAR在炎症中具有有效的抗炎和促溶特性，有助于减少炎症性水肿和抗伤害感受。