Harmful Waste Products as Novel Immune Modulators for Treating Inflammatory Arthritis?

Abstract

For many years, reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, and their reaction products, were classically described as harmful by-products of aerobic metabolism capable of causing DNA mutations, lipid peroxidation, and protein oxidation [1]. The identifi cation of enzymes such as superoxide dismutase, catalase, and peroxidase that served to eliminate these waste products rather substantiated this view. It soon became clear, however, that there existed a family of enzymes whose function it was to deliberately generate ROS. The fi rst of these was NADPH oxidase, which is responsible for the respiratory burst in neutrophils and macrophages in response to microbes or infl ammatory cytokines [2]. The catalytic centre of NADPH oxidase is the membrane-associated protein gp91phox (see Glossary) complexed with p22phox. Activation requires association with a phosphorylated form of p47phox (also known as Ncf1), p67phox, and the small GTPase Rac (Figure 1). p47phox defi ciency in humans leads to neutrophil dysfunction and chronic granulomatous disease (CGD), a primary immunodefi ciency disorder characterised by the inability to eradicate bacterial infections [3]. Since the late 1990s, six human gp91phox homologues have been identifi ed, each with distinct functions [1]. Besides a role in phagocyte function and host defence, a large amount of evidence points to important roles for ROS in cell proliferation, apoptosis, angiogenesis, endocrinerelated functions, and oxidative modifi cation of the extracellular matrix. Indeed, increased ROS have been documented at sites of infl ammation, such as synovial joints of patients with infl ammatory arthritis (e.g., rheumatoid arthritis [RA]), and circulating neutrophils and monocytes from patients with RA have increased NADPH oxidase activity [4,5]. Interestingly, polyarthritis has also been described in patients with CGD. More recently, induction of arthritis in mice defi cient for the p47phox subunit of NADPH oxidase was shown to induce granulomatous synovitis and exaggerated matrix destruction associated with enhanced expression of infl ammatory mediators [6]. Although the mechanism for this paradoxical relationship between defi cient NADPH Harmful Waste Products as Novel Immune Modulators for Treating Infl ammatory Arthritis?