Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.

ABSTRACT: 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 wit

SUBMITTER: Umar S 

PROVIDER: S-EPMC9118817 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature