Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19.
Highlights
Nicholas Stoy*Reviewed by: Yi Zheng, Shandong University, China Qi Wang, Harbin Veterinary Research Institute (CAAAS), China
Effective treatments are required for COVID-19 hyperinflammatory syndrome, occurring characteristically 7–14 days after first symptoms [1] and variously described as “macrophage activation syndrome” [2], “cytokine storm” [3] or “acute respiratory distress syndrome” [4]
A challenging complexity of variables influence Interleukin-1 receptor-associated kinase 4 (IRAK4)-interferon regulatory factor 5 (IRF5) pathway activation outcomes [55]: these include different IRF5 dimerization partners—including homodimerization and IRF7 [56]; functionally different IRF5 isoforms, as investigated in plasmacytoid dendritic cells (DCs) [57]; IRF5 interacting with different transcription factors [17], most critically the NF-κB subunits, p50 [48, 58], and/or p65(RELA) [41, 59, 60]; different cellular localizations, notably monocytes, macrophages, pDCs, and B cells [55, 58, 61]; different triggers of pathway activation, for e.g., viral infection or autoimmunity; inhibition of the IRF5mediated activation of IFN-β by the IKKα pathway [62]; and differences between murine and human cells [63]—all beyond the scope of this review
Summary
Reviewed by: Yi Zheng, Shandong University, China Qi Wang, Harbin Veterinary Research Institute (CAAAS), China. Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. A case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
