The IL-1 receptor-associated kinases (IRAKs) are components of the signalling cascade responding to IL-1 receptor family (IL-1R, IL-18R, IL-33R) and pathogen recognition Toll-like receptor (TLR) activation [7]. IL-1/TLR/IRAK activity is critical for the innate immune response to pathogens [6].

The IRAK family consists of four members, IRAK1, IRAK2, IRAK3 (also known as IRAK-M) and IRAK4. Only IRAK1 and IRAK4 have verified kinase activity [15]. Whilst IRAKs 1, 2 and 4 are ubiquitously expressed, IRAK3 expression is restricted to monocytes and macrophages.

Dysregulated IRAK4 activity triggers the release of inflammatory cytokines and chemokines and underlies increased autoimmune signalling in disease pathology [14,19-20]. In contrast, IRAK4 deficiency in humans (caused by loss-of-function mutations and/or loss of protein expression [3,5,12,17,24]) results in recurrent infections from early infancy, with sufferers unable to produce pro-inflammatory cytokines in response to IL-1R or TLR engagement or to sustain antibody responses [4,16]. IRAKs may also be involved in tumourigenesis [18].

Due to experimentally proven links with a wide range of diseases, extensive drug discovery effort is being dedicated to develop IRAK inhibitors with clinical efficacy [2]. IRAK4 is of particular interest [9,22-23] due to its pivotal role in mediating IL-1R and TLR signals upstream of IRAK1 [11,13], and because of its involvement in NF-κB phosphorylation in response to pathogen insult [10].

Findings published by Sun et al. (2016) [21] report differential requirements for IRAK proteins in the TLR pathway between mouse and human macrophages. This study concludes that results obtained from mouse models of macrophage TLR signalling may be limited in their relevance to human disease. This is an important finding because of the ongoing drug development effort in this field, with medicinal chemists on the trail of IRAK inhibitors as potential immunotherapeutics (e.g. IRAK-1/4 inhibitor, and the IRAK4 selective inhibitors compound 1 [WO2012007375] [1], and ND-2158 which has preclinical activity in autoimmune disorders and lymphoid malignancy [8]).

1. Arora N, Chen S, Hermann JC, KuglstatterA, Labadie SS, Lin CJJ, Lucas MC, Moore AG, Papp E, Talamas FX et al.. (2012) Pyrazolo [1, 5a] pyrimidine and thieno [3, 2b] pyrimidine derivatives as irak4 modulators. Patent number: WO2012007375. Assignee: F. Hoffmann-La Roche Ag. Priority date: 13/11/2015. Publication date: 19/01/2012.

2. Chaudhary D, Robinson S, Romero DL. (2015) Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders. J Med Chem, 58 (1): 96-110. [PMID:25479567]

3. Davidson DJ, Currie AJ, Bowdish DM, Brown KL, Rosenberger CM, Ma RC, Bylund J, Campsall PA, Puel A, Picard C et al.. (2006) IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. J Immunol, 177 (11): 8202-11. [PMID:17114497]

4. Day N, Tangsinmankong N, Ochs H, Rucker R, Picard C, Casanova JL, Haraguchi S, Good R. (2004) Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr, 144 (4): 524-6. [PMID:15069404]

5. Enders A, Pannicke U, Berner R, Henneke P, Radlinger K, Schwarz K, Ehl S. (2004) Two siblings with lethal pneumococcal meningitis in a family with a mutation in Interleukin-1 receptor-associated kinase 4. J Pediatr, 145 (5): 698-700. [PMID:15520784]

6. Flannery S, Bowie AG. (2010) The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling. Biochem Pharmacol, 80 (12): 1981-91. [PMID:20599782]

7. Henderson C, Goldbach-Mansky R. (2010) Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: finding the right balance in response to danger signals. Clin Immunol, 135 (2): 210-22. [PMID:20353899]

8. Kelly PN, Romero DL, Yang Y, Shaffer 3rd AL, Chaudhary D, Robinson S, Miao W, Rui L, Westlin WF, Kapeller R et al.. (2015) Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J Exp Med, 212 (13): 2189-201. [PMID:26621451]

9. Kondo M, Tahara A, Hayashi K, Abe M, Inami H, Ishikawa T, Ito H, Tomura Y. (2014) Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats. Naunyn Schmiedebergs Arch Pharmacol, 387 (10): 909-19. [PMID:25052043]

10. Koziczak-Holbro M, Glück A, Tschopp C, Mathison JC, Gram H. (2008) IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes. Eur J Immunol, 38 (3): 788-96. [PMID:18266302]

11. Koziczak-Holbro M, Littlewood-Evans A, Pöllinger B, Kovarik J, Dawson J, Zenke G, Burkhart C, Müller M, Gram H. (2009) The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation. Arthritis Rheum, 60 (6): 1661-71. [PMID:19479877]

12. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J et al.. (2007) Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med, 204 (10): 2407-22. [PMID:17893200]

13. Li S, Strelow A, Fontana EJ, Wesche H. (2002) IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA, 99 (8): 5567-72. [PMID:11960013]

14. Lye E, Dhanji S, Calzascia T, Elford AR, Ohashi PS. (2008) IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. Eur J Immunol, 38 (3): 870-6. [PMID:18286567]

15. Lye E, Mirtsos C, Suzuki N, Suzuki S, Yeh WC. (2004) The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem, 279 (39): 40653-8. [PMID:15292196]

16. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med, 198 (4): 521-31. [PMID:12925671]

17. Medvedev AE, Thomas K, Awomoyi A, Kuhns DB, Gallin JI, Li X, Vogel SN. (2005) Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex. J Immunol, 174 (11): 6587-91. [PMID:15905496]

18. Rhyasen GW, Starczynowski DT. (2015) IRAK signalling in cancer. Br J Cancer, 112 (2): 232-7. [PMID:25290089]

19. Silver MR, Margulis A, Wood N, Goldman SJ, Kasaian M, Chaudhary D. (2010) IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation. Inflamm Res, 59 (3): 207-18. [PMID:19763788]

20. Staschke KA, Dong S, Saha J, Zhao J, Brooks NA, Hepburn DL, Xia J, Gulen MF, Kang Z, Altuntas CZ et al.. (2009) IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. J Immunol, 183 (1): 568-77. [PMID:19542468]

21. Sun J, Li N, Oh KS, Dutta B, Vayttaden SJ, Lin B, Ebert TS, De Nardo D, Davis J, Bagirzadeh R et al.. (2016) Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci Signal, 9 (409): ra3. [PMID:26732763]

22. Tumey LN, Boschelli DH, Bhagirath N, Shim J, Murphy EA, Goodwin D, Bennett EM, Wang M, Lin LL, Press B et al.. (2014) Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4. Bioorg Med Chem Lett, 24 (9): 2066-72. [PMID:24726805]

23. Wang Z, Wesche H, Stevens T, Walker N, Yeh WC. (2009) IRAK-4 inhibitors for inflammation. Curr Top Med Chem, 9 (8): 724-37. [PMID:19689377]

24. Yamamoto T, Tsutsumi N, Tochio H, Ohnishi H, Kubota K, Kato Z, Shirakawa M, Kondo N. (2014) Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol Immunol, 58 (1): 66-76. [PMID:24316379]