Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.
Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.
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DOI：
10.1007/s00018-022-04329-8
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发表时间：
2022-05-19
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影响因子：
--
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天然免疫增强在SARS-CoV-2病理学中起着关键作用;然而，其分子机制尚不完全清楚。因此，我们的目标是表征SARS-CoV-2刺突蛋白推进人类巨噬细胞（M β）炎症和糖酵解表型的分子机制，并发现新的治疗策略。我们发现暴露于Spike蛋白的人M β激活IRAK 4磷酸化。阻断刺突蛋白刺激的MLS中的IRAK 4使IRAK 4、AKT和基线p38的信号传导无效，而不影响ERK和NF-κB活化。有趣的是，IRAK 4抑制剂（IRAK 4 i）挽救了ACE 2 +HEK 293细胞中SARS-CoV-2诱导的细胞毒性效应。此外，IRAK 4 i通过IRF 5和IRF 7减弱了刺突蛋白对M细胞的炎性重编程，沿着单核因子、IL-6、IL-8、TNFα和CCL 2的减少。值得注意的是，在刺突蛋白刺激的M细胞中，IRAK 4 i对炎症标志物的抑制与氧化磷酸化对代谢活性的再平衡相结合。IRAK 4 i在刺突蛋白激活的巨噬细胞中促进的这种代谢适应部分通过抑制PFKBF 3、HIF 1 α、cMYC、LDHA、乳酸表达以及柠檬酸盐和琥珀酸盐积累的逆转来实现。IRAK 4敲低可显著损害人巨噬细胞中Spike蛋白增强的炎症和代谢印记，如用ACE 2、TLR 2和TLR 7 siRNA处理的那些。扩展这些结果，在小鼠模型中，其中人SARS-CoV-2刺突蛋白不被小鼠ACE 2识别，TLR负责由刺突蛋白引发的炎症和糖酵解反应，并且被IRAK 4 i治疗失调。总之，IRAK 4 i可能是一个有前途的策略，严重的COVID-19患者通过反调节ACE 2和TLR介导的M β超活化。IRAK 4 i疗法抵消由刺突蛋白触发的M β炎性和糖酵解重编程。这项研究表明，SARS-CoV-2刺突蛋白激活IRAK 4信号通过ACE 2以及TLR 2和TLR 7在人类骨髓细胞中的传感。值得注意的是，IRAK 4 i治疗可以使ACE依赖性和非依赖性（通过TLR传感）SARS-CoV-2刺突蛋白激活的炎症和代谢印记失调。在线版本包含补充材料，可通过10.1007/s 00018 -022-04329-8获取。
Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (Mϴ) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human Mϴs exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated Mϴs nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-κB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2+HEK 293 cells. Moreover, the inflammatory reprogramming of Mϴs by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFα, and CCL2. Notably, in Spike protein-stimulated Mϴs, suppression of the inflammatory markers by IRAK4i was coupled with the rebalancing of oxidative phosphorylation over metabolic activity. This metabolic adaptation promoted by IRAK4i in Spike protein-activated Mϴs was shown to be in part through constraining PFKBF3, HIF1α, cMYC, LDHA, lactate expression, and reversal of citrate and succinate buildup. IRAK4 knockdown could comparably impair Spike protein-enhanced inflammatory and metabolic imprints in human Mϴs as those treated with ACE2, TLR2, and TLR7 siRNA. Extending these results, in murine models, where human SARS-CoV-2 Spike protein was not recognized by mouse ACE2, TLRs were responsible for the inflammatory and glycolytic responses instigated by Spike protein and were dysregulated by IRAK4i therapy. In conclusion, IRAK4i may be a promising strategy for severe COVID-19 patients by counter-regulating ACE2 and TLR-mediated Mϴ hyperactivation. IRAK4i therapy counteracts Mϴ inflammatory and glycolytic reprogramming triggered by Spike protein. This study illustrates that SARS-CoV-2 Spike protein activates IRAK4 signaling via ACE2 as well as TLR2 and TLR7 sensing in human Mϴs. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints. The online version contains supplementary material available at 10.1007/s00018-022-04329-8.
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DOI：
10.1084/jem.20201707
发表时间：
2021-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Rodrigues TS;de Sá KSG;Ishimoto AY;Becerra A;Oliveira S;Almeida L;Gonçalves AV;Perucello DB;Andrade WA;Castro R;Veras FP;Toller-Kawahisa JE;Nascimento DC;de Lima MHF;Silva CMS;Caetite DB;Martins RB;Castro IA;Pontelli MC;de Barros FC;do Amaral NB;Giannini MC;Bonjorno LP;Lopes MIF;Santana RC;Vilar FC;Auxiliadora-Martins M;Luppino-Assad R;de Almeida SCL;de Oliveira FR;Batah SS;Siyuan L;Benatti MN;Cunha TM;Alves-Filho JC;Cunha FQ;Cunha LD;Frantz FG;Kohlsdorf T;Fabro AT;Arruda E;de Oliveira RDR;Louzada-Junior P;Zamboni DS
通讯作者：
Zamboni DS
影响因子：
27.4
作者：
Chamberlain ND;Kim SJ;Vila OM;Volin MV;Volkov S;Pope RM;Arami S;Mandelin AM 2nd;Shahrara S
通讯作者：
Shahrara S
影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
影响因子：
3.7
作者：
Neerukonda SN;Vassell R;Herrup R;Liu S;Wang T;Takeda K;Yang Y;Lin TL;Wang W;Weiss CD
通讯作者：
Weiss CD
影响因子：
4.6
作者：
Sugiyama MG;Cui H;Redka DS;Karimzadeh M;Rujas E;Maan H;Hayat S;Cheung K;Misra R;McPhee JB;Viirre RD;Haller A;Botelho RJ;Karshafian R;Sabatinos SA;Fairn GD;Madani Tonekaboni SA;Windemuth A;Julien JP;Shahani V;MacKinnon SS;Wang B;Antonescu CN
通讯作者：
Antonescu CN