INTRODUCTION

IRAK4 and TLR/IL-1R Signalling Pathways

The Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that are central to innate immune signalling [1,2]. TLRs are characterized by an extracellular immunoglobulin (Ig) domain and intracellular Toll-interleukin (TIR) domain. The interleukin-1 (IL-1) receptor family is another transmembrane TIR domain-containing receptor family that is stimulated by a variety of IL-1 family cytokines, thereby initiating immune responses [3]. Immune responses initiated by TLRs can be activated by the recognition of protein-associated molecular patterns, such as viral- or bacterial-associated molecules, or damage-associated molecular patterns (DAMPs), including cytokines and other molecules which result from cellular degradation pathways [4,5]. Upon activation of these receptors, their cytoplasmic TIR domain recruits adapter proteins, resulting in the formation of the myddosome complex, comprised of adaptor protein myeloid differentiation primary response gene 88 (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 2 (IRAK2), and interleukin-1 receptor-associated kinase 4 (IRAK4) [6].

IRAK4 is a serine—threonine kinase crucial in the signalling cascade, which initiates the production of proinflammatory cytokines through NF-KB-mediated and mitogen-activated protein kinase (MAPK) activation, as well as IFNa/p secretion through interferon response factors 3 and 7 (IRF3/7) [7—10]. Upon recruitment of IRAK4 to MyD88, through an interaction with the kinase death domain, activation of IRAK4 leads to the phosphorylation of IRAK1 and/or IRAK2. This effects the recruitment of tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) [11,12]. Subsequent signalling through kinases TAK1 to IKKa results in the activation ofNF-KB and the production of proinflammatory cytokines IL-1, IL-8, and IL-33; as well as, other chemokines attributed to disease pathology, including the type I IFNs. It is important to note that IRAK4 is central to all MyD88-dependent signalling, making it an attractive therapeutic target for suppressing uncharacteristic and prolonged inflammatory responses that may contribute to the progression of diseases involving innate or adaptive immunity (Fig. 1).

Validation of IRAK4 as a target for therapeutic intervention has been investigated based on the identification of a small human population deficient in IRAK4 [13]. Blood samples from the IRAK4-deficient patients

Interleukin-1 receptor and Toll-like receptor signalling cascade

Fig. 1 Interleukin-1 receptor and Toll-like receptor signalling cascade.

show a reduced response to TLR agonism as NF-kB and MAPK-induced cytokines were not observed upon exposure to LPS (lipopolysaccharide, a potent TLR4 agonist). The IRAK4-dependent human TLRs appear to be essential in childhood immunity, as the patient population is susceptible to recurrent pneumococcal and staphylococcal infections. However, interestingly, the IRAK4-dependent human TLRs are not crucial for protective immunity, as adaptive immunity seems to compensate for the weak innate immune response as the patients age [14].

Given the strong human genetic validation of IRAK4 pathway biology, kinase-dead knock-in mice (IRAK4 KD) have been generated to elucidate the effects on downstream signalling with respect to kinase function [15—17]. Reports indicate that IRAK4 KD mice have reduced IL-1-induced NF-kB activation compared to wild-type, while further studies employing joint inflammation animal models have established that IRAK4 KD mice are protected from inflammation when stimulated with LPS [18]. Furthermore, it has been reported that IRAK4-deficient mice are resistant to a lethal dose of LPS [19]. The genetic evidence provided by the human IRAK4 null subjects, and rodent data validating IRAK4 kinase function, suggests that IRAK4 is a viable target for therapeutic intervention for treating disorders related to IL-1R and TLR signal transduction. A number of therapies have been approved to treat cytokine-mediated inflammatory diseases, such as the IL-1 receptor antagonist anakinra (Kineret®) and the anti-TNF-a monoclonal antibody adalimumab (Humira®) [20]. As an IRAK4 kinase inhibitor is expected to limit the production of IL-1, TNF-a, and other proinflammatory mediators, intercepting this signalling pathway could have greater therapeutic benefit than either of the marketed therapeutics. This hypothesis has led to an abundance of literature reflecting research into potent and selective IRAK4 inhibitors [21—24].

 
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