Interleukin-17A Aggravates Middle Ear Injury Induced by Streptococcus pneumoniae through the p38 Mitogen-Activated Protein Kinase Signaling Pathway

Abstract

Acute otitis media (AOM) is one of the most common bacterial infectious diseases in children aged 2 to 7 years worldwide. We previously demonstrated that interleukin-17A (IL-17A) promotes an acute inflammatory response characterized by the influx of neutrophils into the middle ear cavity during Streptococcus pneumoniae-induced AOM. In general, the inflammatory response is viewed as an effector that frequently causes local tissue damage. However, little is known about the pathogenic effects of IL-17A in AOM. Here, we investigated the pathogenic effects of IL-17A by using wild-type (WT) and IL-17A knockout (KO) mouse models. The results showed that the pathogenic effects of AOM, including weight loss, histopathological changes, and proinflammatory cytokine production, were more severe in WT mice than in IL-17A KO mice, suggesting that IL-17A aggravates tissue damage in AOM. Furthermore, these pathogenic effects were found to be dependent on p38 mitogen-activated protein kinase (MAPK) and could be reversed in the presence of a p38 MAPK-specific inhibitor. It was also demonstrated that IL-17A promoted the production of neutrophil myeloperoxidase (MPO) through the p38 MAPK signaling pathway, which was responsible for the middle ear tissue injury. These data support the conclusion that IL-17A contributes to middle ear injury through the p38 MAPK signaling pathway. KEYWORDS acute otitis media, IL-17A, injury, MPO, neutrophilsA cute otitis media (AOM) is one of the most common infectious diseases in the pediatric population (1). According to data from the United States, about 50% to 85% of children have suffered from at least one episode of AOM by the age of 3 years (2). The annual cost for the diagnosis and treatment of AOM approaches $3 billion in the United States alone (3). A lack of timely and effective treatment for AOM often leads to some serious complications, such as permanent hearing loss and meningitis (3, 4). Pathogenic bacteria exist in up to 70% of middle ear fluid specimens from patients with AOM, and 50% of the bacterial cases are induced by Streptococcus pneumoniae. Other common pathogens include nontypeable Haemophilus influenzae and Moraxella catarrhalis (5-7). As a result, the clinical management of AOM relies heavily on antibiotic therapies (4), which may promote the emergence of antibiotic-resistant strains of

Correlation between Serum Interleukin-17 level and Serum Reactive Oxygen Species levels among Children experiencing Otitis Media with Effusion

“…Previous studies have established the involvement of the IL-17 pathway in the pathogenesis of OME. 9 While IL-17 exerts its local proinflammatory effects, it is systemically produced and adjusts many types of cells, including fibroblasts, macrophages, endothelial cells, and epithelial cells to mobilize the immunological cells to the inflammatory site. 18 The present study suggests that IL-17 exacerbates OME by stimulating ROS (MPO, MDA, NO, and CT), through finding a significantly higher level of ROS in patients with OME than in their healthy controls.…”

“…Previous studies have established the involvement of the IL-17 pathway in the pathogenesis of OME. 9 …”

“…8 The study of Wang et al showed that IL-17 induced middle ear effusion by stimulating the release of myeloperoxidase (MPO) oxidative enzyme, which has a significant function in chronic inflammation. 9 Reactive oxygen species (ROS) are essential pathological mediators of numerous diseases. Reactive oxygen species, which are created during metabolic and chemical reactions, may contain ingredients that induce toxicity in numerous tissues, such as hydroxyl free radicals, hydrogen peroxide, lipid peroxides, hydroxyl peroxide, and other derivatives.…”

“…8 The study of Wang et al showed that IL-17 induced middle ear effusion by stimulating the release of myeloperoxidase (MPO) oxidative enzyme, which has a significant function in chronic inflammation. 9 …”

Current Understanding of Host Genetics of Otitis Media

“…The same group found that IL-17A also induces ME injury since IL-17A knockout (KO) mice display less severe pathological changes in their ME and lower pro-inflammatory cytokine and myeloperoxidase (MPO) levels. Furthermore, the group showed that neutrophil MPO production is mediated by the p38 MAPK signaling pathway (Wang et al, 2017).…”