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Review
. 2011 Jun;89(6):873-91.
doi: 10.1189/jlb.1010550. Epub 2011 Jan 13.

Nitric oxide and redox mechanisms in the immune response

David A Wink  1 , Harry B Hines, Robert Y S Cheng, Christopher H Switzer, Wilmarie Flores-Santana, Michael P Vitek, Lisa A Ridnour, Carol A Colton
Affiliations
Review

Nitric oxide and redox mechanisms in the immune response

David A Wink et al. J Leukoc Biol. 2011 Jun.

Abstract

The role of redox molecules, such as NO and ROS, as key mediators of immunity has recently garnered renewed interest and appreciation. To regulate immune responses, these species trigger the eradication of pathogens on the one hand and modulate immunosuppression during tissue-restoration and wound-healing processes on the other. In the acidic environment of the phagosome, a variety of RNS and ROS is produced, thereby providing a cauldron of redox chemistry, which is the first line in fighting infection. Interestingly, fluctuations in the levels of these same reactive intermediates orchestrate other phases of the immune response. NO activates specific signal transduction pathways in tumor cells, endothelial cells, and monocytes in a concentration-dependent manner. As ROS can react directly with NO-forming RNS, NO bioavailability and therefore, NO response(s) are changed. The NO/ROS balance is also important during Th1 to Th2 transition. In this review, we discuss the chemistry of NO and ROS in the context of antipathogen activity and immune regulation and also discuss similarities and differences between murine and human production of these intermediates.

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Figures

Figure 1.
Figure 1.. The immunotoxic and immunoregulatory aspects of redox-based biology.
The redox species and sources are: NO and RNS derived from NOS; ROS derived from NOX; arachidonic acid products derived from COX and lipoxygenase (LOX); CO derived from HO-1; and H2S from CBS and cystathionine β-lyase (CBL). Of the multiple redox species involved in immunity, NO/RNS and ROS are critical to defense against pathogens and for regulation of the response.
Figure 2.
Figure 2.. The NO chemistry of the phagosome.
This diagram depicts the different nitrogen oxide and ROS chemistry that can occur within the phagosome to fight pathogens. The presence of NOX2 in the phagosomes serves two purposes: one is to focus the nitrite accumulation through scavenging mechanisms, and the second provides peroxide as a source of ROS or FA generation. The nitrite (NO2−) formed in the acidic environment provides nitrosative stress with NO/NO2/N2O3. The combined acidic nature and the ability to form multiple RNS and ROS within the acidic environment of the phagosome provide the immune response with multiple chemical options with which it can combat bacteria.
Figure 3.
Figure 3.. Diagrammatic view of critical interactive connections between NO and ROS-mediated metabolic pathways.
DHFR, Dihydrofolate reductase; SAH, S-adenosyl-HCys; ODC, ornithine decarboxylase.
Figure 4.
Figure 4.. The effect of steady-state flux of NO on signal transduction mechanisms.
This diagram represents the level of sustained NO that is required to activate specific pathways in tumor cells. Similar effects have been seen on endothelial cells. These data were generated by treating tumor or endothelial cells with the NO donor DETANO (NOC-18) for 24 h and then measuring the appropriate outcome measures (for example, p53 activation). Various concentrations of DETANO that correspond to cellular levels of NO are: 40–60 μM DETANO = 50 nM NO; 80–120 μM DETANO = 100 nM NO; 500 μM DETANO = 400 nM NO; and 1 mM DETANO = 1 μM NO. The diagram represents the effect of diffusion of NO with distance from the point source (an activated murine macrophage producing iNOS) in vitro (Petri dish) generating 1 μM NO or more. Thus, reactants or cells located at a specific distance from the point source (i.e., iNOS, represented by star) would be exposed to a level of NO that governs a specific subset of physiological or pathophysiological reactions. The x-axis represents the different zone of NO-mediated events that is experienced at a specific distance from a source iNOS producing >1 μM. Note: Akt activation is regulated by NO at two different sites and by two different concentration levels of NO.
Figure 5.
Figure 5.. Comparison of the promoter region of NOS2 between human and murine.
Promoters′ information was obtained from the Genomatix Software Suite. Each bar represents a particular transcription factor binding site. Upward bars represent the bind site located on the sense strand of the DNA, and downward bars represent the binding sites located on the nonsense strand. IRF, IFN regulatory factor; PARP, poly(ADP-ribose) polymerase; RXR-α, retinoid X receptor α; E-BOX, E-box binding factors, contains binding domains bHLH-ZIP and bZIP; KLF6, Kruppel-like factor 6.
Figure 6.
Figure 6.. Mechanisms of NO that activate a Th1 phenotypic response.
For description of regulated pathways, please see text.
Figure 7.
Figure 7.. Mechanisms of NO in immunosuppression and tissue restoration.
For description of regulated pathways, please see text.
Figure 8.
Figure 8.. A flow diagram of NO in inflammation and tissue-restoration response.
Blue lines represent the linear progression from initial insult to tissue restoration. A fatal loop is found in diseases such as cancer, where the processes are restimulated, and leads to chronic conditions or a “wound that never heals”. The lines in red show pathways that contribute to perpetuation of chronic disease and failure to resolve tissue-restoration processes correctly.
Figure 9.
Figure 9.. A summary of levels of NO required to elicit different mechanisms of the inflammation and tissue-restoration response.
See this image and copyright information in PMC

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