**Neutrophils in Rheumatoid Arthritis: A Target for Discovering New Therapies Based on Natural Products**

Elaine Cruz Rosas, Luana Barbosa Correa and Maria das Graças Henriques

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68617

#### **Abstract**

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88 Role of Neutrophils in Disease Pathogenesis

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Rheumatoid arthritis (RA) is a systemic autoimmune disorder with an important inflammatory component in joints. Neutrophils are the most abundant leukocytes in inflamed joints, and play an essential role in the initiation and progression of RA. Neutrophil effector mechanisms include the release of proinflammatory cytokines, reactive oxygen and nitrogen species (ROS and RNS), and granules containing degradative enzymes, which can cause further damage to the tissue and amplify the neutrophil response. Therefore, the modulation of neutrophil migration and functions is a potential target for pharmacological intervention in arthritis. The pharmacologic treatment options for RA are diverse. The current treatments are mostly symptomatic and have side effects, high costs, and an increased risk of malignancies. Because of these limitations, there is a growing interest in the use of natural products as therapies or adjunct therapies. Herbal products have attracted considerable interest over the past decade because of their multiple beneficial effects such as their antioxidant, anti-inflammatory, antiproliferative, and immunomodulatory properties. This chapter focuses on the role of neutrophils in the pathogenesis of arthritis and the action of substances from natural products as putative antirheumatic therapies.

**Keywords:** neutrophils, rheumatoid arthritis, herbal products, polyphenols, flavonoids, tetranortriterpenoids, inflammation

## **1. Introduction**

Arthritis is an inflammatory joint disorder that can cause edema, pain, and loss of function. The most common types of arthritis are osteoarthritis, gout, and rheumatoid arthritis [1, 2]. Rheumatoid arthritis is a systemic, autoimmune disorder with an important inflammatory

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

component in which genetic and environmental risk factors contribute to disease development. Its prevalence in the world population is between 0.3 and 1%, and it affects three times more women than men [3, 4].

The pathophysiology of RA is complex and appears to be initiated when the adaptive immune system (cellular or humoral) recognizes self-joint antigens as non-self, which triggers a variety of distinct inflammatory effector mechanisms, including the recruitment of leukocytes [5–8].

RA is characterized by intense inflammatory processes and joint damage that are mediated by the influx of immune system cells to the synovial space such as neutrophils, macrophages, and lymphocytes [1, 2]. A critical factor that contributes to tissue damage is the excessive production of inflammatory mediators by resident and/or infiltrated cells. Among the primary mediators involved in joint damage are free radicals, enzymes that degrade the matrix, and pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, as well as chemokines such as CXCL-8, lipid mediators, such as leukotriene B<sup>4</sup> (LTB<sup>4</sup> ) [9, 10], and endothelin (ET) [11, 12]. Inflamed synovial tissue is invasive and called pannus, which can be formed by synovial cell proliferation, angiogenesis, and the accumulation of macrophages, lymphocytes, and neutrophils [13].

Neutrophils are crucial cells that have significant roles in diverse inflammatory diseases, including acute, chronic, autoimmune, infectious, and non-infectious conditions [14]. The most wellknown effector function of neutrophils is their role in innate immunity. However, recent studies have identified neutrophils as active cells during adaptive immunity, facilitating the recruitment and activation of antigen-presenting cells or directly interacting with T cells. Neutrophils are the most abundant leukocytes in inflamed joints, and the importance of these cells in the initiation and progression of human RA as well as in murine models has been demonstrated [15–18]. Therefore, neutrophils play an essential role in joint inflammation, and the modulation of neutrophil functions is considered a potential target for pharmacological intervention in arthritis [19–21].

The pharmacologic treatment options for arthritis are diverse. The current treatments are mostly symptomatic and include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologic therapies. High costs and an increased risk of malignancies limit the use of these agents, in addition to the potential side effects that all therapies possess. Plant-derived products, such as polyphenols, sesquiterpenes, flavonoids, and tetranortriterpenoids, which are herbal metabolites with anti-inflammatory activity, may provide new therapeutic agents and cost-effective treatments [22, 23]. This chapter focuses on the role of neutrophils in the pathogenesis of arthritis and the action of substances from natural products as putative antirheumatic therapies.
