Regulation of innate immune signaling by IRAK proteins

Pereira, Milton; Gazzinelli, Ricardo T.

doi:10.3389/fimmu.2023.1133354

Cited by 28 publications

(23 citation statements)

References 183 publications

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“…IRAK-M belongs to the IRAK family but is known to lack kinase activity ( 84 ). IRAK-M is also popularly known as IRAK3 and has been studied in the negative regulation of inflammatory states associated with TLRs ( Figure 1 ) ( 85 , 86 ). IRAK-M is contrarian in function compared to the other members of the family.…”

Section: Interleukin-1 Receptor-associated Kinase-mmentioning

confidence: 99%

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Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

Baig,

Barmpoutsi,

Bharti

et al. 2024

Front. Immunol.

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Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages’ activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.

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Section: Interleukin-1 Receptor-associated Kinase-mmentioning

confidence: 99%

“…IRAK-M interacts with other proteins in the family through its DD. The lack of an aspartate residue in its active site has been postulated as the main reason for the lack of kinase activity ( 85 , 87 ).…”

Section: Interleukin-1 Receptor-associated Kinase-mmentioning

confidence: 99%

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

Baig,

Barmpoutsi,

Bharti

et al. 2024

Front. Immunol.

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“…Most TLRs and all IL-1Rs signal through the myddosome, a complex of proteins that includes IL-1 receptor–associated kinase 4 (IRAK4), which is assembled upon activation of MYD88 (refs. 10 , 11 ). A master regulator of innate immunity, IRAK4 has scaffolding and kinase functions that are essential for downstream signaling through nuclear factor (NF)-κB, mitogen-activated protein (MAP) kinases and IRF5 and IRF7 (refs.…”

Section: Mainmentioning

confidence: 99%

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial

Ackerman,

Acloque,

Bacchelli

et al. 2023

Nat Med

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Toll-like receptor–driven and interleukin-1 (IL-1) receptor–driven inflammation mediated by IL-1 receptor–associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600–1,600 mg and after 14 daily doses of ≥95% at 50–200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885.

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“…Interaction of this complex with IRAK1 or IRAK2 leads to the autophosphorylation of IRAK4, followed by the phosphorylation of IRAK1 or IRAK2 . Via further steps, the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways are activated. , Finally, activation of this MyD88–IRAK4 pathway promotes other processes associated with inflammation and inflammatory pain, including the increased expression of different inflammatory signaling molecules and enzymes (cytokines, chemokines, and cyclooxygenase-2 [COX-2]) and the enhancement of mRNA stability for various inflammation-associated genes. , In addition, processes associated with the proliferation and differentiation of certain cell types, especially immune cells, are affected. , …”

Section: Introductionmentioning

confidence: 99%

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

Bothe,

Günther,

Nubbemeyer

et al. 2024

J. Med. Chem.

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Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer’s compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

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Regulation of innate immune signaling by IRAK proteins

Cited by 28 publications

References 183 publications

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

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