Impaired Cytokine Signaling in Mice Lacking the IL-1 Receptor-Associated Kinase

Abstract

Stimulation of the type 1 IL-1R (IL-1R1) and the IL-18R by their cognate ligands induces recruitment of the IL-1R-associated kinase (IRAK). Activation of IRAK leads in turn to nuclear translocation of NF-κB, which directs expression of innate and adaptive immune response genes. To study IRAK function in cytokine signaling, we generated cells and mice lacking the IRAK protein. IRAK-deficient fibroblasts show diminished activation of NF-κB when stimulated with IL-1. Immune effector cells without IRAK exhibit a defective IFN-γ response to costimulation with IL-18. Furthermore, mice lacking the Irak gene demonstrate an attenuated response to injected IL-1. Deletion of Irak, however, does not affect the ability of mice to develop delayed-type hypersensitivity or clear infection with the intracellular parasite, Listeria monocytogenes. These results demonstrate that although IRAK participates in IL-1 and IL-18 signal transduction, residual cytokine responsiveness operates through an IRAK-independent pathway.

A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage

“…IRAK1 inhibitors showed efficacy in zebrafish and mammalian models of tumor R-RT at doses tolerated by non-irradiated tissues. The therapeutic window suggested by this data, in line with the absence of overt phenotypes in Irak1 —/— mice (Thomas et al, 1999), overcomes the limitations of traditional radiosensitizers and is of urgent need in the clinic (Lawrence et al, 2013; Sharma et al, 2016). Our present work identifies multiple immunofluorescence markers of RT-induced IRAK1 signaling which could be used as diagnostic tools to predict IRAK1i treatment efficacy in patient biopsies, as well as new pathway members (IRAK4, Peli1, Peli2, ATR) which might define additional targets for inhibition.…”

Regulation of innate immune signaling by IRAK proteins

“…This model is consistent with the observation that IRAK1 and IRAK2 are redundant at early time-points, but IRAK2 is required for later responses ( Figure 4 ) ( 67 ). However, other cell types require IRAK1 ( 43 ). The molecular basis for this preference is unknown but may involve differences in IRAK1 and IRAK2 expression levels, half-life, splice variants, and regulation by additional molecules.…”

“…Further study in human cells identified IRAK, a protein that shared high similarity to Pelle, responsible for activation of a NF-κB homolog in Drosophila ( 18 ). Generation of IRAK knockout mice, however, revealed that in vivo responses to IL-1β or IL-18 were only partially blocked, suggesting the existence of an alternative pathway ( 43 ). Additionally, Irak1 -/- mice challenged with LPS showed only a subtle improvement in survival, further suggesting an alternative pathway ( 143 ).…”

“…This partial redundancy, however, appears to be context dependent. For instance, Irak1 -/- mouse embryonic fibroblasts fail to activate NF-κB in response to IL-1β or IL-18 ( 43 ), whereas Irak1 -/- macrophages activate NF-κB unimpaired in response to a variety of TLR agonists ( 67 , 77 ). In humans, IRAK1-deficient macrophages are greatly deficient in TNF production, while IRAK2 deficiency has little to no impact, opposite to what is observed in mouse macrophages ( 136 ).…”

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

“…All IRAKs proteins share similar domain organization, consisting of a conserved N-terminal domain (death domain) essential for dimerization and interaction with the MyD88, a proline/serine/threonine-rich (ProST) domain, and a kinase and/or pseudokinase domain [ 45 ] (Fig. 3 A).…”