**3. NOx versus prokaryote: "Catch me if you can"**

of the signal leads to the transcription of NF-κB [60]. This transcription factor is essential for the expression of *iNOS* gene. On the other hand, cytokines produced by infected cells activate pathways responsible for the expression of several transcription factors (NF-κB, AP1, and IRF1) also involved in the transcription of iNOS [61]. Both pathways are necessary to fully upregulate iNOS expression. Moreover, iNOS is constitutively active and exhibits a high affinity for calcium explaining its Ca2+-independent activity. iNOS produces a large amount of NO until substrate

generated through the reaction of NO with ROS formed by NADPH oxidase. These molecules can be generated inside (phagosome) or outside the cells. Altogether, NO and derivatives could act in synergy on several components within the targeted hostile elements such as proteins (thiols, metal centers, and tyrosine residues), nucleic acids, and lipids [63, 64]. Altogether, these modifications lead to irreversible damages impairing cellular metabolism and ultimately inhibit

After infection, NO generation is abolished by neutralization of iNOS activity. Indeed, iNOS undergoes a posttranslational modification called polyubiquitination leading to its proteasomal degradation. Physiological aggresome, an alternative pathway for protein degradation, is also involved in iNOS inactivation [66]. The degradation of NO can also be modulated by its own interaction with ROS. The depletion of l-arginine precursor also shuts down iNOS activity.

Overexpression of iNOS is observed during chronic infection leading to an excessive level of NO and RNS. This phenomenon can impair the host physiology because these high reactive compounds represent mutagenic sources. Thus, the NO balance is a crucial point to

**Figure 11.** Implication of iNOS in the innate immunity (adapted from [65]). IFNϒ, interferon ϒ; IFNR1/2, IFNϒ receptors 1 and 2; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IRF1, interferon response factor 1; IL1β, interleukin 1β; IL1R, IL1β receptor; MAPK, mitogen-activated protein kinase; JNK, C-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; AP1, activator protein 1; TNF-α, tumor necrosis factor α; TNFR, tumor necrosis factor receptor; NF-κB, nuclear factor κB; TLR4, Toll-like receptor 4; CD14, cluster of differentiation 14; LPS,

lipopolysaccharide; LPB, LPS-binding protein; ROS, reactive oxygen species.

and NO2

)

depletion [62]. Then, NO acts directly or through derived compounds (mostly ONOO<sup>−</sup>

growth and replication mechanisms and even cell death (**Figure 11**).

30 Emerging Pollutants - Some Strategies for the Quality Preservation of Our Environment
