NADPH Oxidases in Innate Immunity

and Duox in the respiratory epithelium. The location of these ROS-generating enzymes in the barrier tissues has prompted the expectation of their participation in host defense against invading pathogens in these tissues. Indeed, recent studies have begun to support this expectation, demonstrating roles in bacterial killing, cytokine production, apoptosis, gene expression and signaling, including by pattern-recognition receptors [2–6] . The papers in the current Journal of Innate Immunity thematic issue on ‘NADPH oxidases and innate immunity’ address a variety of aspects of Nox family function and regulation. The initial review by Quinn and Schlepetkin [7] provides an interesting and comprehensive exploration of a little-known and poorly understood aspect of the innate immune response: the role of Nox-generated ROS in macrophage fusion. Depending on the tissue and the inflammatory stimulus, phagocytic macrophages can fuse to form giant, multinucleated cells that serve as important mediators of tissue remodeling and repair, as well as of the removal of bacteria and other pathogens. This review provides an up-to-date overview of the role(s) of multinucleated macrophages in inflammation and autoimmune disorders. The following papers focus on aspects of the phagocyte NADPH oxidase, Nox2. Munafo et al. [8] investigate the phenomena of neutrophil extracellular trap (NET) formation and their interaction with Nox2. NETs consist of extracellular complexes of DNA fibers, histones and granule-derived bactericidal proteins extruded from subsets of activated neutrophils [9] . NET formation requires a specialized form of cell death that is distinct from apopThe controlled enzymatic generation of reactive oxygen species (ROS) by phagocytic leukocytes is an integral component of the innate immune response. While highlevel formation of ROS by phagocytes was long recognized as a means to kill ingested pathogens, we now know that ROS at lower levels can have intracellular signaling activity. The formation of these short-lived, but reactive oxygen metabolites, which include superoxide anion, hydrogen peroxide, hydroxyl radical and others, is catalyzed in leukocytes by the membrane-associated enzyme, NADPH oxidase. This multi-component enzyme consists of both membrane-bound components (Nox2, p22 phox ) and cytosolic regulatory proteins (p40 phox , p47 phox , p67 phox and Rac2 GTPase). While much is understood about the assembly and activation of the phagocyte enzyme during the innate immune response, our knowledge remains far from complete. It is now recognized that the phagocyte NADPH oxidase is a member of a ubiquitous family of NADPH oxidases (or Nox). The 7 Nox family members (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2) are homologous, each with 6-membrane-spanning domains and a cytoplasmic NADPH/FAD-containing electron transfer domain [1] . Nox1, Nox2, Nox3 and Nox4 form natural heterodimers with membrane-associated p22 phox , but Nox5 and the Duox appear to not require p22 phox for either stability or function. While the Nox family members are found throughout many tissues and cell types, it is of particular interest that several Nox are abundant in so-called ‘barrier’ tissues or epithelia. Thus, Nox1 is abundant in the gastrointestinal epithelium, Nox4 in the vasculature Published online: August 27, 2009 Journal of Innate Immunity