Metabolic reprogramming of macrophages instigates CCL21-induced arthritis.
Metabolic reprogramming of macrophages instigates CCL21-induced arthritis.
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巨噬细胞代谢重编程引发ccl21诱导的关节炎。
DOI：
10.1111/imcb.12512
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发表时间：
2022-03
影响因子：
4
通讯作者：
Shahrara S
中科院分区：
文献类型：
--
作者：
Van Raemdonck K;Umar S;Palasiewicz K;Meyer A;Volin MV;Chang HJ;Al-Awqati M;Zomorrodi RK;Shahrara S
本研究旨在阐明CCL 21对实验性关节炎和类风湿性关节炎（RA）分化的巨噬细胞（MΦs）代谢重编程的功能意义。为了表征CCL 21对免疫代谢的影响，通过临床前关节炎和RA MΦ中葡萄糖摄取的失调来阐明其作用机制。在CCL 21关节炎关节中，糖酵解中间产物HIF 1 α、cMYC和GLUT 1的表达高于氧化调节因子ESSRγ和PGC 1 α。有趣的是，2-DG治疗通过抑制关节F480 +iNOS+ M Φ的数量而不影响F480+精氨酸酶+MΦ来减轻CCL 21诱导的关节炎。与临床前研究结果相似，糖酵解的阻断否定了CCL 21极化的CD 14 + CD 86 +GLUT+MΦ频率;然而，CD 14 + CD 206 +GLUT+MΦ与该过程无关。在CCL 21诱导的关节炎和分化的RA MΦ中，炎症印记通过IL-6下调被2-DG独特地拦截。尽管如此，相对于分化的RA MΦs，2-DG，关节炎关节中CCL 21的更广泛的炎症反应对关节TNFα、IL-1β、CCL 2和CCL 5富集无效。相反，糖酵解的破坏显著损害了关节炎小鼠中CCL 21诱导的HIF 1 α和cMYC信号传导。值得注意的是，在RA MΦs中，糖酵解拦截针对CCL 21增强的HIF 1 α转录的失调。尽管如此，在IL-6水平降低的同时，糖酵解和HIIF 1 α抑制逆转了CD 14 + CD 86 + GLUT 1 +MΦs的CCL 21-分化。此外，在CCL 21实验性关节炎或分化的RA MΦ中，代谢机制故障伴随着由于PGC 1 α或PPARγ表达减少而导致的氧化磷酸化受损。CCL 21可将幼稚的骨髓细胞重组为糖酵解性RA CD 14 + CD 86 +GLUT+IL-6 highHIF 1 α highM Φs，因此抑制CCL 21/CCR 7通路可能提供一种有前景的治疗策略。在这项研究中，我们发现，CCL-21诱导的关节炎是逆转的糖酵解失调。此外，巨噬细胞引发的炎症以及CCL 21的糖酵解印记通过IL-6和HIF 1 α逆转。
The current study was designed to delineate the functional significance of CCL21 on metabolic reprogramming in experimental arthritis and rheumatoid arthritis (RA) differentiated macrophages (MΦs). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA MΦs. In CCL21 arthritic joints, the glycolytic intermediates, HIF1α, cMYC, and GLUT1 were overexpressed compared to oxidative regulators, ESSRγ and PGC1α. Interestingly, 2-DG therapy mitigated CCL21-induced arthritis by restraining the number of joint F480+iNOS+MΦs without impacting F480+Arginase+MΦs. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14+CD86+GLUT+MΦ frequency; however, CD14+CD206+GLUT+MΦs were not implicated in this process. In CCL21-induced arthritis and differentiated RA MΦs, the inflammatory imprint was uniquely intercepted by 2-DG via IL-6 downregulation. Despite, the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA MΦs, 2-DG was ineffective on joint TNFα, IL-1β, CCL2, and CCL5 enrichment. In contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1α and cMYC signaling in arthritic mice. Notably, in RA MΦs, glycolysis interception was directed on dysregulating CCL21-enhanced HIF1α transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21-differentiation of CD14+CD86+GLUT1+MΦs was reversed by glycolysis and HIIF1α inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA MΦs, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation due to reduced PGC1α or PPARγ expression. CCL21 reconfigures naïve myeloid cells into glycolytic RA CD14+CD86+GLUT+IL-6highHIF1αhigh MΦs, thus inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy. In this study we found that CCL-21-induced arthritis is reversed by dysregulation of glycolysis. Additionally, macrophage-instigated inflammation as well as glycolytic imprints of CCL21 are reversed via IL-6 and HIF1α.
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影响因子：
5.8
作者：
McGarry T;Hanlon MM;Marzaioli V;Cunningham CC;Krishna V;Murray K;Hurson C;Gallagher P;Nagpal S;Veale DJ;Fearon U
通讯作者：
Fearon U
影响因子：
4.3
作者：
Jaguin, Marie;Houlbert, Noemie;Lecureur, Valerie
通讯作者：
Lecureur, Valerie
三种类型的吞噬细胞中的代谢模式。
影响因子：
7.8
作者：
OREN, R;FARNHAM, A E;SAITO, K;MILOFSKY, E;KARNOVSKY, M L
通讯作者：
KARNOVSKY, M L
影响因子：
2.1
作者：
Liang, Huiyun;Ward, Walter F.
通讯作者：
Ward, Walter F.
影响因子：
32.4
作者：
Liu, Juan;Zhang, Xiaomin;Cao, Xuetao
通讯作者：
Cao, Xuetao