Peroxynitrite, a potent macrophage‐derived oxidizing cytotoxin to combat invading pathogens

Abstract

Macrophages are among the first cellular actors facing the invasion of microorganisms. These cells are able to internalize pathogens and destroy them by means of toxic mediators, many of which are produced enzymatically and have strong oxidizing capacity. Indeed, macrophages count on the NADPH oxidase complex activity, which is triggered during pathogen invasion and leads to the production of superoxide radical inside the phagosome. At the same time, the induction of nitric oxide synthase results in the production of nitric oxide in the cytosol which is able to readily diffuse to the phagocytic vacuole. Superoxide radical and nitric oxide react at diffusion controlled rates with each other inside the phagosome to yield peroxynitrite, a powerful oxidant capable to kill microorganisms. Peroxynitrite toxicity resides on oxidations and nitrations of biomolecules in the target cell. The central role of peroxynitrite as a key effector molecule in the control of infections has been proven in a wide number of models. However, some microorganisms and virulent strains adapt to survive inside the potentially hostile oxidizing microenvironment of the phagosome by either impeding peroxynitrite formation or rapidly detoxifying it once formed. In this context, the outcome of the infection process is a result of the interplay between the macrophage-derived oxidizing cytotoxins such as peroxynitrite and the antioxidant defense machinery of the invading pathogens.

Cytochrome bd from Escherichia coli catalyzes peroxynitrite decomposition

“…This prompted us to investigate in the present study the interaction of E. coli cytochrome bd with ONOO − , another highly reactive species produced by the host to combat microbial pathogens, that is known to give rise to oxidative and nitrosative stresses in E. coli [71] and other microorganisms (reviewed in [2]). The aim of this work was twofold: on the one hand to determine whether the enzyme is irreversibly inhibited by ONOO − , thus representing a potential target for ONOO − in the E. coli cell, and on the other hand to test if cytochrome bd can metabolize ONOO − .…”

“…Peroxynitrite (ONOO − ) is a cytotoxic effector produced in mammalian immune cells to kill invading microbes (reviewed in [1,2]). In response to microbial infections, macrophages generate simultaneously nitric oxide (NO•) and superoxide anion (O 2 − •) by activating the inducible nitric oxide synthase (iNOS) and NADPH oxidase, respectively.…”

Adaptation of Candida albicans to Reactive Sulfur Species

“…These ROS and RNS include chemicals such as hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO), respectively, which are used in humans as defense mechanisms against invading pathogens (Hromatka et al 2005; Dantas et al 2015). Especially toxic are the products of the interactions between ROS and RNS, such as peroxynitrite, generated in macrophages by the reaction of nitric oxide with superoxide (McLean et al 2010;Prolo et al 2014). Moreover, NO reacts with cysteine thiols to form S-nitrosothiols (SNO), an effective inhibitor of Gram-positive bacteria and fungi (Finnen et al 2007;Cariello et al 2012).…”

TRAP-positive osteoclast precursors mediate ROS/NO-dependent bactericidal activity via TLR4

“…Since the production of NO and ROS is significantly promoted in macrophage phagocytosis [17,18], we hypothesized that NO and ROS produced by RANKL-stimulated RAW264.7 cells could kill the phagocytized bacteria. To test this idea, RAW264.7 cells, both unstimulated and prestimulated with RANKL for 48 h and 96 h, incubated with E. coli induced a significantly elevated production of ROS (Fig.…”

“…Activation of TLRs induces macrophages to produce proinflammatory mediators, such as nitric oxide (NO), reactive oxygen species (ROS; e.g., peroxides, superoxide and hydroxyl radical), TNFα and IL-1b [15,16]. Among them, NO and ROS accumulated in phagolysosomes are significantly engaged in bactericidal effects on bacteria phagocytosed by macrophages [17,18]. Interestingly, it is reported that ROS, including superoxide and hydrogen peroxide, are crucial components that upregulate osteoclast differentiation [19–21].…”