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

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 antigen‐specific IgG production and frequency of antigen‐specific 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.