*2.2.5 Sepsis*

In septic patients, the loss of redox balance is usually the common cause of severe inflammatory response syndrome. The inflammation is caused by the reactive species from neutrophils and macrophages. The inflammation phase of the disease is marked by reduced mitochondrial ATP synthesis and continuous uptake of antioxidants by

#### *Reactive Oxygen Species in the Development and Resolution of Autoimmune and Inflammatory… DOI: http://dx.doi.org/10.5772/intechopen.99988*

affected cells. The antioxidants aim to fight the deleterious activity of ROS and RNS such as reversible and irreversible oxidative modifications of nucleic acids, lipids, and proteins. The oxidative modification of complex lipids of the mitochondrial inner membrane such as cardiolipin worsens the mitochondrial dysfunction by causing the release of cytochrome c [56, 57]. This causes further reduction of ATP synthesis while elevating the production of reactive species. Excessive and persistent ROS in turn inhibits the translocation of Nrf2, which jeopardizes the antioxidant response mechanism.

#### *2.2.6 Psoriasis*

Psoriasis is an immune-mediated chronic inflammatory skin disease that speeds up the growth cycle of skin cells. The disease comprises numerous comorbidities and the multifactorial etiology of cardiovascular diseases, metabolic syndrome, and type 2 diabetes [58]. The pathogenesis of psoriasis is heavily marked by oxidative stress. However, ROS is reported to have protective effects in psoriasis. In mice models with induced psoriasis, elevated levels of ROS will increase the functionality of T regulator cells as well as the expression of indoleamine 2,3-dioxygenase. Increased functionality of T regulator cells results in the reduction of circulating Th17 cells [20]. The protective effects of ROS are further supported by evidence showing the exacerbation of Psoriasis in Ncf1 mutated mice [59]. This suggests that the normal functionality of NOX2 plays a role in the attenuation of psoriasis.

#### *2.2.7 Gout*

Gout is one of the most understood and manageable systemic rheumatoid diseases. It is a disorder of purine metabolism that results in the formation of monosodium urate crystals that are deposited in and around the joints. This is mostly due to longstanding hyperuricemia. The urate crystals can induce the release of inflammatory cytokines from monocytes and neutrophils, which cause immense inflammation [60]. The onset of gout attack can last for at most 10 days and then disappear, but the crystals remain present in the joint area. These crystals can induce the formation of large NETs aggregates that end up trapping and degrading the pro-inflammatory mediators. This in turn will limit and resolve the inflammation [61]. The formation of NETs in gout is dependent on the availability of ROS, and a deficiency in ROS can result in a chronic state for the disease. Therefore, a functional oxidative burst is critical for the maintenance of immune tolerance and the resolution of inflammation in gout.

## **3. ROS in inflammation resolution and autoimmune regulation**

The effects of ROSs autoimmunity appears to be more complicated than previously anticipated. ROS is thought to be solely a by-product of the process involved in the cellular response to inflammation or infectious stimuli. However, recent findings have attributed ROS to have vital roles in cellular regulatory and inflammation restraining processes. As their role in numerous cell functions is elaborated, it is now understood that these functions cannot occur without the presence of ROSs. Despite this, the tissue, cell type and time point on which ROS act as anti-inflammatory and immunoregulators are not yet elucidated.

The deficiency of NOX2 has been found to play a key role in the induction of multiple autoimmunity conditions. This is true even in severe bacterial and fungal infections. Inflammatory and autoimmune diseases such as Corhn-like inflammatory disease, idiopathic arthritis and CGD can co-occur. Animal model experiments as well as genome-wide studies have shown a relationship between the polymorphism of Ncf1 and the occurrence of many arthritic diseases [62]. Ncf1 is a cytosolic subunit of NOX2 whose polymorphism signifies diminished production of superoxide. Mutation in the Ncf1 gene which results in loss of NOX2 function has been reported to increase susceptibility to T cell autoreactive activation, cartilage oligomeric matric proteininduced arthritis, and collagen-induced arthritis among others [28]. Additionally, NOX2 derived ROS have been found to have regulatory roles in T-cell dependent nervous system diseases such as multiple sclerosis and Guillan-barre syndrome. Interestingly, NOX2 is also a regulator of autoantibody production and autoimmune inflammation. Therefore, NOX2 activity, especially ROS generation has a crucial preventative effect on the development of autoimmunity and can regulate chronic inflammation [63]. However, it is important that NOX2 is viewed not as a regulator of disease susceptibility but as a regulator of disease severity.

The protective role of ROS in inflammatory and autoimmunity is not universal. In type 1 diabetes, ROS deficiency is associated with safeguarding from diseases, especially in non-obese diabetic animal model. Thayer et al. reported the essential role of macrophage ROS in mediating effector function for CD4+ T cells autoreactivity and autoimmune diabetes pathogenesis [64]. NOX2 generated ROS is also vital in the execution of islet reactivity. However, mutations in the Ncf1 gene which eventually leads to NOX2 malfunction and reduced ROS availability has been found to significantly alter the effector function of macrophages and T-cell subsets [43]. Additionally, collagen antibody transfer which develops independently of phagocytic immune cells can induce arthritis. This phenomenon can be exacerbated by an increase of Ncf1 gene expression. Furthermore, non-classical autoimmune diseases such as monosodium urate crystal-induced inflammation and zymosan show signs of increased inflammation even in the absence of NOX2 and ROS [41, 63]. This shows that certain cases ROS deficiency can be linked to the protection against disease.
