Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.
Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.
复制标题
DOI：
10.1007/s00018-021-03978-5
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Shahrara S
中科院分区：
文献类型：
--
作者：
Umar S;Palasiewicz K;Volin MV;Romay B;Rahat R;Tetali C;Arami S;Guma M;Ascoli C;Sweiss N;Zomorrodi RK;O'Neill LAJ;Shahrara S
最近的研究表明代谢重编程在免疫和基质细胞功能中的重要性。然而，在活动性疾病期间以及实验性关节炎中与其他细胞类型的串扰中，RA 巨噬细胞 (MΦs) 的代谢重构尚不完全清楚。这项研究阐明了与成纤维细胞 (FLS) 相比，RA MΦ 中糖酵解和氧化磷酸化的独特调节，尽管 PPP 在两种细胞类型中进行了类似的重新配置。 2-DG 治疗通过逆转 ERK、AKT 和 STAT1 信号传导、IRF8/3 转录以及 CCL2 或 CCL5 分泌，对损害 RA M1 MΦ 介导的炎症表型产生比 IACS-010759（IACS，complexli）更强大的影响。 2-DG 疗法对 RA M1 MΦs 的这种更广泛的抑制作用与糖酵解（GLUT1、PFKFB3、LDHA、乳酸）和氧化 PPP（NADP 转化为 NADPH）的失调有关，而这两种化合物对氧化磷酸化无效。明显地，在 RA FLS 中，2-DG 和 IACS 疗法限制了 LPS/IFNγ 诱导的 AKT 和 JNK 信号传导、IRF5/7 和纤维因子表达。 2-DG 或 IACS 治疗对 RA FLS 代谢重连的破坏伴随着糖酵解（HIF1α、PFKFB3）的减少以及柠檬酸盐或琥珀酸盐积聚的抑制。我们发现 2-DG 疗法通过阻断 F480+iNOS+MΦ、波形蛋白+成纤维细胞和 CD3+T 细胞的联合运输以及 IRF 和糖酵解中间体的下调来减轻 CIA 病理。令人惊讶的是，IACS 治疗对 CIA 肿胀、细胞浸润、M1 和 Th1/Th17 细胞因子以及关节糖酵解介质无关紧要。总的来说，我们的结果表明，在 CIA 中，阻断糖酵解比抑制复合物更有效，部分原因是其对 MΦ 炎症表型的有效性。
Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription, and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT & JNK signaling, IRF5/7, and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480+iNOS+MΦ, Vimentin+fibroblast & CD3+T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 & Th1/Th17 cytokines, and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complexl in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.
登录
查看更多内容
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD
影响因子：
168.9
作者：
McInnes, Iain B.;Schett, Georg
通讯作者：
Schett, Georg
影响因子：
13.6
作者：
Elshabrawy HA;Essani AE;Szekanecz Z;Fox DA;Shahrara S
通讯作者：
Shahrara S
影响因子：
7.3
作者：
Abboud G;Choi SC;Kanda N;Zeumer-Spataro L;Roopenian DC;Morel L
通讯作者：
Morel L