Role of leukotriene B4 receptors in rheumatoid arthritis

Abstract

The purpose of this review is to summarize the role that murine models of arthritis are playing in the understanding of human rheumatoid arthritis and how leukotriene B(4) (LTB(4)) is emerging as an important target in this field. Both the collagen-induced arthritis (CIA) model and the K/BxN serum transfer arthritis model have contributed to outline the potential mechanisms involved in inflammatory arthritis. Indeed, the CIA model has contributed to the development of effective anti-TNFalpha and anti-IL-1beta based treatments for RA that are currently in the clinic. Many recent studies in mouse models have suggested a critical role for LTB(4) and its receptors in the development of inflammatory arthritis. Inhibitors of LTB(4) biosynthesis as well as LTB(4) receptors are protective in mouse models of RA and mice deficient in the LTB(4) biosynthetic enzymes or LTB(4) receptors are resistant to disease development suggesting several promising targets for RA in this pathway.

Figure 1. The role of LTB₄ in the development of arthritis

LTB₄, a pro-inflammatory lipid mediator, is synthesized from the arachidonic acid pathway involving the biosynthetic enzymes 5-lipoxygenase (5-LO), Five-Lipoxygenase Activating Protein (FLAP) and LTA₄ Hydrolase (LTA₄H) via 5HPETE and LTA₄ as intermediates. Arthritis might be initiated by infection mediated activation in the joints and/or from the formation of auto-antibodies leading to deposition of immune complexes (IC) in the synovium. The immune complexes activate mast cells and cause mast cell degranulation, which further leads to the influx of inflammatory cells through vasodilation and other mediators. Interplay of synovial cells and the incoming leukocytes leads to production of cytokines and activation of the complement cascade. Amplification loops between the cytokines and chemoattractants like LTB₄ and other chemokines sets up perpetual joint inflammation. All of the innate immune cells such as dendritic cells, macrophages, neutrophils and mast cells are capable of producing LTB₄ by the induction of complement or cytokines. Since all of these cells express LTB₄ receptors they set up further amplification loops in the inflamed joints. The solid lines represent response to and broken lines represent production of indicated mediators.