Interleukin‐1 receptor–associated kinase 4 links innate immunity to the pathogenesis of rheumatoid arthritis

Abstract

The innate immune response is linked to the adaptive immune response through several families of the pattern recognition receptors, among which Toll-like receptors (TLRs) are the most studied. Triggering of the pattern recognition receptors results in production of cytokines and chemokines and enhancement of both innate and adaptive immune responses. TLR signaling pathways share similar elements with interleukin-1 receptor (IL-1R)/IL-18R signaling pathways. Activation of the receptors after ligand binding leads to the recruitment of the Toll/IL-1R domain–containing adaptor molecule, myeloid differentiation factor 88, to the TLRs (1). Thereafter, several kinases such as IL-1R–associated kinase 4 (IRAK-4) and IRAK-1, as well as tumor necrosis factor receptor–associated factor 6, are recruited to the receptor complex (Figure 1). IRAK-4 is activated, and after hyperphosphorylation of IRAK-1, the receptor complex is further activated by transforming growth factor –activated kinase 1–dependent and –independent pathways, leading finally to activation of the downstream mediators NFB and activator protein 1 (2,3). An important factor in the activation of this inflammatory pathway is IRAK-4. IRAK-4 is a member of a family of protein kinases that also contains IRAK-1, IRAK-2, and IRAK-M. It has been demonstrated that IRAK-4 is crucial for the signaling pathway of the IL-1 and IL-18 receptors. In addition, IRAK-4 is needed for activation of nearly all of the TLRs, with the exception of TLR-3. Using IRAK-4 kinase-inactive knockin mice, it has been shown that IRAK-4 is important for IL-1–, lipopolysaccharide (LPS; TLR-4)–, or R848 (TLR-7)– induced cytokine and chemokine production (4–6). Interestingly, TLR-4 signaling is only partly disrupted in IRAK-4 kinase-inactive knockin mice, since cells from these mice respond to LPS exposure with subnormal cytokine production (7). The partial TLR-4 responsiveness is mediated by a secondary pathway involving the TRIF adaptor molecule (Figure 1). However, IRAK-4 kinase-inactive knockin mice are resistant to LPSor CpG-induced lethal shock (5). The role of active IRAK-4 has not been extensively studied in animal models of complex diseases. Very recently, it was shown that IRAK-4 is crucial in the development of vascular inflammation. IRAK-4 kinaseinactive knockin mice backcrossed in apolipoprotein E–knockout mice were almost completely protected against atherosclerosis (8). However, until now very little has been known about the effect of IRAK-4 in models of arthritis. In this issue of Arthritis & Rheumatism, KoziczakHolbro and colleagues demonstrate for the first time that IRAK-4 kinase-inactive knockin mice are completely protected against the development of antibodyinduced arthritis (K/BxN mouse model). Compared with wild-type (WT) mice, IRAK-4 kinase-inactive knockin mice did not have joint swelling, cartilage damage, or bone erosions (9). It has been previously shown that this particular animal model of arthritis is highly IL-1 dependent, since IL-1–deficient mice were extremely resistant to the K/BxN model of experimental arthritis (10). In line with these results, Koziczak-Holbro and colleagues confirmed the critical role of IRAK-4 in the IL-1R signaling pathway (9). Interestingly, however, the authors also showed that IRAK-4 kinase activity was not necessary for trafficking of T cells, B cells, and macrophages to the site of inflammation, whereas IRAK-4 was crucial for residential stromal cells to recruit inflammatory cells to the joint. These data identify IRAK-4 as a pivotal upstream kinase and potential therapeutic target to modulate synoviocyte activation in rheumatoid arthritis (RA). Furthermore, Koziczak-Holbro and colleagues Leo A. B. Joosten, PhD, Mihai G. Netea, MD, PhD: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Address correspondence and reprint requests to Leo A. B. Joosten, PhD, Department of Medicine (463), Radboud University Nijmegen Medical Centre, Geert Grooteplein zuid 8, 6525 GA Nijmegen, The Netherlands. E-mail: l.joosten@aig.umcn.nl. Submitted for publication February 3, 2009; accepted in revised form February 25, 2009.