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10.1007/s00018-022-04329-8 http://scihub22266oqcxt.onion/10.1007/s00018-022-04329-8 35588018!9118817!35588018     free     free     free Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Cell+Mol+Life+Sci 2022 ; 79 (6): 301 Nephropedia Template TP {{tp|p=35588018|t=2022. Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming |pdf=|usr=}}{{35588018}} gab.com Text Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming JO: Cell Mol Life Sci http://www.kidney.de/pget.php?&tw=1&pmid=35588018 #FOAvip 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 (M?) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human M?s exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated M?s nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-kappaB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2(+)HEK 293 cells. Moreover, the inflammatory reprogramming of M?s by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFalpha, and CCL2. Notably, in Spike protein-stimulated M?s, 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 M?s was shown to be in part through constraining PFKBF3, HIF1alpha, 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 M?s 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 M? hyperactivation. IRAK4i therapy counteracts M? 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 M?s. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints. Twit Text FOAVip Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming ????Cell Mol Life Sci http://www.kidney.de/pget.php?&tw=1&pmid=35588018 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=35588018 #FOAvip English Wikipedia <ref>{{Cite pmid|35588018}}</ref> Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming #MMPMID35588018 Umar S; Palasiewicz K; Meyer A; Kumar P; Prabhakar BS; Volin MV; Rahat R; Al-Awqati M; Chang HJ; Zomorrodi RK; Rehman J; Shahrara S Cell Mol Life Sci 2022[May]; 79 (6): 301 PMID35588018show ga 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 (M?) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human M?s exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated M?s nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-kappaB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2(+)HEK 293 cells. Moreover, the inflammatory reprogramming of M?s by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFalpha, and CCL2. Notably, in Spike protein-stimulated M?s, 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 M?s was shown to be in part through constraining PFKBF3, HIF1alpha, 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 M?s 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 M? hyperactivation. IRAK4i therapy counteracts M? 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 M?s. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints. |*COVID-19[MESH] |*Spike Glycoprotein, Coronavirus/genetics/metabolism[MESH] |Angiotensin-Converting Enzyme 2[MESH] |Animals[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Interferon Regulatory Factors/metabolism/pharmacology[MESH] |Interleukin-1 Receptor-Associated Kinases/genetics/metabolism[MESH] |Macrophages/metabolism[MESH] |Mice[MESH] |SARS-CoV-2[MESH] |Toll-Like Receptor 2/metabolism[MESH]Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macr(epmc).pdf DeepDyve Pubget Overpricing