The critical role of kinase activity of interleukin‐1 receptor–associated kinase 4 in animal models of joint inflammation

Abstract

Objective. We have previously reported that the kinase activity of interleukin-1 receptor-associated kinase 4 (IRAK-4) is important for Toll-like receptor and interleukin-1 receptor signaling in vitro. Using mice devoid of IRAK-4 kinase activity (IRAK-4 KD mice), we undertook this study to determine the importance of IRAK-4 kinase function in complex disease models of joint inflammation.Methods. IRAK-4 KD mice were subjected to serum transfer-induced (K/BxN) arthritis, and migration of transferred spleen lymphocytes into joints and cartilage and bone degradation were assessed. T cell response in vivo was tested in antigen-induced arthritis (AIA) by measuring the T cell-dependent antigenspecific IgG production and frequency of antigenspecific T cells in the spleen and lymph nodes. T cell allogeneic response was tested in vitro by mixed lymphocyte reaction (MLR).Results. Lipopolysaccharide-induced local neutrophil influx into subcutaneous air pouches was impaired in IRAK-4 KD mice. These mice were also protected from inflammation in the K/BxN and AIA models, as shown by reduced swelling of joints. Histologic analysis of joints of K/BxN serum-injected mice revealed that bone erosion, osteoclast formation, and cartilage matrix proteoglycan loss were reduced in IRAK-4 KD mice. Assessment of T cell response by MLR, by frequency of antigen-specific clones, and by production of antigen-specific IgG did not reveal substantial differences between IRAK-4 KD and wild-type mice.Conclusion. These results demonstrate that IRAK-4 is a key component for the development of proarthritis inflammation, but that it is not crucial for T cell activation. Therefore, the kinase function of IRAK-4 appears to be an attractive therapeutic target in chronic inflammation.

Membrane-Bound Toll-Like Receptors are Overexpressed in Peripheral Blood and Synovial Fluid Mononuclear Cells of Enthesitis-Related Arthritis Category of Juvenile Idiopathic Arthritis (JIA–ERA) Patients and Lead to Secretion of Inflammatory Mediators

“…While the role of these proteins has not been extensively investigated in humans, there are several animal models to show that knocking out these adaptors results in protection from disease. KBxN mice having inactive IRAK4 [27] were completely protected against arthritis. IRAK1-deficient mice have reduced IL-17 production and increased Foxp3 expression [28].…”

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

“…These gene-deficient mice, however, do not allow discrimination of kinase versus nonkinase functions. IRAK4 KD knock-in mice have revealed an essential role for IRAK4 kinase activity in pDC IFN-a and macrophage responses to IL-1b and TLR7 (19,20,37), whereas its role in T cell responses is unclear because of conflicting data (20,(38)(39)(40). Because IRAK1 KD knock-in mice have not been reported, the kinase-specific role of IRAK1 in various signaling pathways is unresolved.…”

Interleukin 1/Toll-like Receptor-induced Autophosphorylation Activates Interleukin 1 Receptor-associated Kinase 4 and Controls Cytokine Induction in a Cell Type-specific Manner

“…The death domain of MyD88 then recruits the kinases IRAK1 and IRAK4 into a signaling complex and associates with them via their death domains. It has been demonstrated that mice with a targeted deletion or a kinase-inactive version of IRAK4 are protected from disease in models of rheumatoid arthritis, atherosclerosis, multiple sclerosis, and Alzheimer disease (1)(2)(3)(4)(5). Thus, IRAK4 is an enticing candidate for drug discovery of therapies for these diseases (1)(2)(3)(4)(5).…”