Elsevier

Molecular Aspects of Medicine

Volume 22, Issues 4–5, August–October 2001, Pages 189-216
Molecular Aspects of Medicine

Review
Redox signaling in macrophages

https://doi.org/10.1016/S0098-2997(01)00010-3Get rights and content

Abstract

Macrophages are phagocytic cells that produce and release reactive oxygen species (ROS) in response to phagocytosis or stimulation with various agents. The enzyme responsible for the production of superoxide and hydrogen peroxide is a multi-component NADPH oxidase that requires assembly at the plasma membrane to function as an oxidase. In addition to participating in bacterial killing, ROS, which have recently been shown to be produced enzymatically by non-phagocytic cells, have been implicated in inflammation and tissue injury. These toxic effects have been largely explored over the years and these studies have overshadowed initial observations supporting a role for ROS in modulating cellular function. In recent years, it has become increasingly evident that ROS can function as second messengers and, at low levels, can activate signaling pathways resulting in a broad array of physiological responses from cell proliferation to gene expression and apoptosis. Macrophages can also produce large amounts of nitric oxide (nitrogen monoxide, NO). NO was first identified as the endothelial-derived relaxing factor, EDRF and its role in the signaling pathway leading to its physiological effect was rapidly established. The ability of NO to react with O2radical dot to produce peroxynitrite (ONOO) was later recognized. As it is diffusion-limited, this reaction is more likely to occur in cells like macrophages that produce both ROS and RNS. In this review, we will summarize the current knowledge in redox signaling, and describe more specifically studies that are particular to macrophages.

Introduction

The ability of cells to communicate with each other and to respond to their environment relies on biological mechanisms that allow the information to travel from the cell surface to the nucleus. These mechanisms referred to as signal transduction pathways have been extensively studied in the context of receptor–ligand interaction. Components of these pathways include second messengers, kinases, phospholipases, and phosphatases, among others. In recent years, it has become increasingly clear that ROS, such as superoxide (O2radical dot) and hydrogen peroxide (H2O2) may act as second messengers. Observations made some twenty years ago had suggested that ROS may play a role in modulating cellular function. Studies done then revealed that exogenous H2O2 could mimic the action of the insulin growth factor (Czech, 1976). Shortly thereafter, insulin and nerve growth factor were shown to stimulate endogenous H2O2 production (Mukherjee et al., 1978, Mukherjee and Mukherjee, 1982). These interesting phenomena were overshadowed by studies concentrating on the role of ROS in the pathology of various diseases, the biochemistry of exogenous toxicants, and the killing of bacteria by phagocytes. The discovery of redox-sensitive transcription factors and that nitric oxide (NO), a free radical produced enzymatically, plays a physiological role in vasodilatation and neurotransmission through activation of soluble guanylate cyclase (Gruetter et al., 1979) further supported the concept that ROS and reactive nitrogen species (RNS) can act as second messengers to modulate signaling pathways. This led to the renaissance of the field of redox signaling (Forman and Cadenas, 1997, Adler et al., 1999, Finkel, 1999, Suzuki et al., 1997, Thannickal and Fanburg, 2000, Ignarro, 2000) and with the accumulation of data in various systems, a clearer picture is emerging of the signaling pathways and specific targets affected by ROS/RNS. Here, we will briefly review some of the new concepts in redox signaling and summarize studies in the macrophage, a hematopoietic cell that plays an essential role in inflammation and has the capability to produce both ROS and RNS.

Section snippets

Oxidative stress vs. redox signaling

The effects of oxidants on signaling pathways are often characterized as resulting from oxidative stress. However, oxidative stress, defined as an imbalance between oxidant exposure and antioxidant protection, entails a range of responses that differ greatly with the type of stress and the sensitivity of the cells that are exposed to it. Severe oxidative stress is associated with threats to cell function and viability, resulting in activation of repair mechanisms or apoptosis and sometimes

Endogenous production of ROS/RNS

Initial studies of redox signaling were performed with exogenous oxidants, mostly added as a bolus. More recently, studies have concentrated on conditions that lead to endogenous production of ROS, although in this case, the amount and source of ROS generated are not always defined. Nitric oxide (NO, nitrogen monoxide) is enzymatically produced by nitric oxide synthases (NOS) through the oxidation of L-arginine by a five-electron oxidative reaction in the presence of oxygen and NADPH (Fig. 2).

ROS and RNS chemistry

As the reactive oxygen and nitrogen species are deemed as second messengers, it is important to discuss whether their properties qualify them as such. Second messengers have four basic characteristics that allow regulation. (1) They are either enzymatically generated or regulated by channels and pumps (2) They are enzymatically degraded. (3) Their concentration rises and falls within a short period, and (4) They are specific in action. In the following section, we will detail some of the

ROS/RNS detection

Determining whether any ROS or RNS are involved in a signaling pathway is made difficult by their fleeting existence and low concentrations, due to their reactivity and the remarkable catalytic capacity of the enzymes that specifically catabolize them. For example, SODs have rate constants near diffusion limitation and the steady-state concentration of O2radical dot has been estimated to be ∼10−11 M. Thus, even a 100-fold transient increase in O2radical dot would be difficult to observe. Furthermore, one cannot

ROS/RNS targets

Many studies in the literature have reported various effects by ROS/RNS on signaling pathways (for reviews see Allen and Tresini, 2000; Forman and Cadenas, 1997, Adler et al., 1999, Finkel, 1999, Suzuki et al., 1997, Thannickal and Fanburg, 2000, Ignarro, 2000). At first, an ambiguous picture of these processes emerged, attributable to several factors such as the great variability in dose and mode of administration of exogenous oxidants, and the diversity in cell types used. A lack of knowledge

Redox signaling in macrophages

The term “macrophage” encompasses different cell types of monocytic origin that acquire particular properties as a function of their environment. Studies regarding the role of oxidants on macrophage function have used both primary cells in humans and rodents and cell lines of various origins, often transformed or derived from tumors. Thus, caution must be exerted not to “generalize” the data, but instead to interpret them within the system used as many differences exist between cell populations

Conclusions

Evidence is accumulating in support of a signaling role for the reactive oxygen species produced by the respiratory burst. It is also important to remember that macrophages are long-lived cells with a less intense respiratory burst as those mounted by neutrophils or eosinophils. Although some studies have shown that ROS can interfere in some of the signaling pathways of neutrophils, this signaling role may not be similar in these cells, as neutrophils from patients with chronic granulomatous

Acknowledgements

As this is a brief review, we could not cite many of the important contributions to this rapidly growing field. Work from our laboratories was supported by a grant from the National Institutes of Health, HL37556 and ES05511. We thank Dr. Dale Dickinson for critical reading of the manuscript and our co-workers for their contributions.

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