**Acknowledgements**

ROS, nitric oxide (NO), COX-2, and PGE<sup>2</sup>

102 Role of Neutrophils in Disease Pathogenesis

role in the pathogenesis of arthritis (**Table 3**).

IL-1, IL-6, and VCAM-1 production [196] (**Table 3**).

**4.5. Curcumin**

**5. Conclusion**

in cell types relevant to the pathogenesis of RA

[179–184]. In *in vivo* studies, EGCG was found to inhibit inflammation in mouse models by affecting the functioning of T cells and neutrophils [185, 186]. IL-8 is the most powerful chemo-attractant for neutrophils in the target tissue. EGCG is a very effective inhibitor of IL-1β and of TNF-α-induced IL-8 and macrophage-inflammatory protein-3α (MIP-3α) expression in different cell types [187–189]. These *in vitro* and *in vivo* observations indicated the efficacy of EGCG and demonstrate that it can modulate multiple signal transduction pathways in a fashion that suppresses the expression of inflammatory mediators that play a

Curcumin (**Figure 2e**) is a yellow-colored polyphenol found in the rhizome of turmeric. It has antioxidant, anti-inflammatory, antiapoptotic, and anticarcinogenic properties [190]. Oral administration of curcumin suppressed type II collagen-induced arthritis (CIA) in mice by reducing cellular infiltration, synovial hyperplasia, cartilage destruction, and bone erosion. Moreover, the production of MMP-1 and MMP-3 was inhibited by curcumin in CIA and in

*In vitro*, it has been reported that curcumin decreases IL-1β-induced expression of the pro-inflammatory cytokine IL-6 and vascular endothelial growth factor (VEGF) in RA-FLS [192]. In addition, curcumin blocks neutrophil recruitment through the inhibition of cellular signaling responsible for actin polymerization in association with the down-regulation of adhesion molecules [193]. It has also been shown to induce apoptosis of RA-FLS (which are resistant to apoptosis) by increasing the expression of the proapoptotic protein Bax and down-regulating the expression of the antiapoptotic protein Bcl-2 [190]. Some molecular mechanisms related to curcumin have been identified. In a human synovial fibroblast cell line (MH7A) stimulated with IL-1β, curcumin blocked the activation of the NF-κB pathway and induced deactivation of the ERK-1/2 pathway [192]. In addition, this polyphenol inhibited activating phosphorylation of protein kinase Cδ (PKCδ) in CIA, RA-FLS, and chondrocytes. Curcumin also suppressed JNK and c-Jun activation in those cells [191]. In a clinical trial with RA patients, curcumin reduced reported pain, tenderness, and swelling of joints [194]. A curcumin-based medicine, Meriva®, demonstrated efficacy in clinical trials with patients with osteoarthritis by reducing reported pain [195]. In another clinical trial, treatment with Meriva® reduced stiffness and physical signs of RA (treadmill test) along with

In RA, neutrophils are key cells that are recognized to play an active role in orchestrating the progress of inflammation, through the release of pro-inflammatory cytokines, ROS, RNS, and NETs, which potentially affect the activities of both neutrophils and other cell types, such as resident mononuclear cells and chondrocytes. In addition, neutrophils participate in the

TNF-α-stimulated RA fibroblast-like synoviocytes (RA-FLS) and chondrocytes [191].

This work was supported by Brazilian grants from Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). L. B. Correa is a student of the post-graduation Program in Cellular and Molecular Biology from Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
