Rip2: a novel therapeutic target for bacteria-induced inflammation?

Abstract

Host immunity against microbial pathogens is mediated by both innate and adaptive immune responses. The adaptive immune response is mediated by T- and B cells, whereas the innate immune response is mediated by macrophages and neutrophils. Cell-surface Toll receptors were first identified in Drosophila and play a crucial role in inducing the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and stimulating host immune cells against microbial products. Homologues of the Drosophila Toll receptors were subsequently found in mammalian immune cells; these receptors are termed Toll-like receptors (TLRs) and play a similar role to Drosophila Toll receptors in PAMP recognition. However, TLR2 and TLR4 have received most attention because they recognize peptidoglycan from Gram-positives and lipopolysaccharide (LPS) from Gram-negatives, respectively. In general, TLR-induced intracellular signalling cascades involve the interleukin (IL)-1/IL-18 pathway, which activates extracellular signal-related kinase (ERK), Jun amino-terminal kinase (JNK) and nuclear factor (NF)-κB. Unlike the surface TLRs, Nod family receptors recognize intracellular PAMPs and induce innate immunity to pathogens. It has been shown that a serine/threonine kinase, Rip2, is involved in the Nod-induced signalling cascades leading to NF-κB activation and cytokine expression, with eventual inflammation.Kobayashi et al. [1xRICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Kobayashi, K. et al. Nature. 2002; 416: 194–199Crossref | PubMed | Scopus (635)See all References][1] have now delineated the role of Rip2 in the induction of the innate and adaptive immune responses after creating a Rip2 knockout (KO) mouse. As the Rip2 KO mouse is viable and fertile, it enables the authors to study the role of Rip2 in a wide variety of immune cells. As the first step, the authors analyzed whether Rip2 plays a role in TLR-mediated signalling and demonstrated that Rip2 mediates the signalling cascades initiated by TLR2, -3 and -4, but not by TLR9. An intracellular bacterium, Listeria monocytogenes, was then used to assess the role of Rip2 in the response to a pathogen – in Rip2-deficient macrophages, the expression of tumour necrosis factor (TNF)-α and IL-6 was attenuated. Furthermore, when they studies the in vivo response to LPS, it was found that Rip2-deficient mice were relatively unresponsive to LPS compared with wild-type mice. The LPS-mediated activation of ERK and JNK in macrophages was then examined and it was shown that these signalling pathways were defective in KO mice. The authors additionally showed that Rip2 is an important component of NF-κB activation induced by Nods in embryonic fibroblasts. Moreover, they used NK cells to show that IL-1/IL-18 signalling is deficient in the Rip2 KO mouse. Finally, they determined the requirement of Rip2 for NF-κB translocation on T cells, the key cell type in the adaptive immune response. Collectively, these findings demonstrate that Rip2 plays a central role in mediating the signalling cascades induced by several TLRs as well as intracellular Nods, thus inducing both innate and adaptive immunity in the host.Overall, this study demonstrates the biological importance of Rip2 in the induction of both innate and adaptive immune responses against pathogenic microorganisms. These findings strongly support the contention that Rip2 is a key target for immune intervention to minimize inflammation during the uncontrolled host response to bacterial pathogens and their products.