Necroptosis Underlies Neutrophilic Inflammation Associated with the Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Abstract

Background Necroptosis is an inflammatory cell death associated with a variety of chronic diseases. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease accompanied by eosinophil and neutrophil infiltration. The role of necroptosis in the pathogenesis of CRSwNP remains elusive. Methods Cell death, including apoptosis, pyroptosis and necroptosis in control sinonasal mucosa and CRSwNP, were analyzed by immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF) staining for cleaved caspase 3, cleaved gasdermin D and p-MLKL, respectively. Correlations between necroptosis, inflammatory cytokines and neutrophil infiltration were assessed and a possible role of necroptosis in CRSwNP was evaluated. Primary nasal polyp cells (DNPCs) were stimulated with damage-associated molecular patterns (DAMPs) including ATP or IL-1α and their expression of inflammatory cytokines was analyzed using RT-PCR. The expression of TNF-α and IFNs in nasal polyps was measured by ELISA; human monocyte THP-1 cells were treated with TNF-α or IFN-γ and cell death was measured by LDH release. Results Necroptosis, rather than apoptosis or pyroptosis, was overtly activated in both eosinophilic and non-eosinophilic CRSwNP as evidenced by the presence of prominent phosphorylation of MLKL compared to controls. The abundance of DAMPs (IL-1α, HMGB1), inflammatory cytokines (IL-6) and chemokines (IL-8, CXCL-1) were all increased especially in non-eosinophilic CRSwNP. The extent of necroptosis was positively correlated with the abundance of DAMPs and cytokines, and neutrophil infiltration in CRSwNP. In DNPCs, ATP and IL-1α induced the expression of IL-8 and CXCL-1. Macrophage was found to be the predominant cell type positive for p-MLKL in CRSwNP. Concomitant treatment with TNF-α and IFN-γ, which were abundantly present in CRSwNP, triggered marked necroptosis in THP-1 cells. Conclusion Necroptosis induced by TNF-α and IFN-γ may facilitate the production and release of a myriad of proinflammatory cytokines and entailed neutrophil infiltration to exacerbate inflammation in CRSwNP.

Inflammatory cell distribution accrediting Th2 inflammation in Sinonasal polyp in Indian Population

“…Studies conducted on Danish and Pennsylvanian populations, also found a male predominance in CRSwNP and the male to female ratio ranged between 1.3 and 2.2. [1][2][3]6 Nasal polyposis is considered to be grouped into eosinophilic and non-eosinophilic types, but among various attempts to further divide the nasal polyps based on inflammatory cells, in one of the subdivisions they can be clustered into five types depending on the presence and predominance of lymphocytes, plasma cells, eosinophils, neutrophils, and mixed inflammatory cells. 3,5,7 This pattern of results about the diverse distribution of type and population of the inflammatory cell can be explained as, sinonasal polyposis, commonly also known as Chronic Rhinosinusitis with Nasal Polyps, i.e., CRSwNP, is characteristically a heterogeneous disease with several etiologies and multiple predisposing factors.…”

“…This type of inflammation is predominant in the Asian population having CRS w Nasal polyposis. 2,3,9 However, the studied population is predominantly of the Mongolian race of Asian counties. In the Aryan race like the Indian population, the Th2 is more predominant than Th17.…”

“…In the United States, 1 to 4 per cent of the population are affected by this disease which is more prevalent in between 45 to 65 years of age group and males are twice more common sufferers than females. [1][2][3] The pathophysiology of CRSwNP showed distinct ethnic and https://doi.org/10.18231/j.ijoas.2022.009 2582-4147/© 2022 Innovative Publication, All rights reserved.…”

Exploring the Role of Staphylococcus aureus in Inflammatory Diseases

“…In chronic sinusitis, insufficient IFN-γ-induced autophagy can lead to the p62-dependent apoptosis of epithelial cells, while TNF-α and IFN-γ-induced necroptosis may promote the production and release of numerous pro-inflammatory cytokines and lead to neutrophil infiltration to exacerbate inflammation in CRSwNP [ 293 , 294 ]. SEB can also stimulate IL-21 expression, and IL-21 can also induce Th17 differentiation [ 89 , 90 ].…”

Triptolide inhibits the Apoptosis and Reactive Oxygen Species Production in Hydrogen Peroxide-Treated Nasal Epithelial Cells by Regulating PTEN/PI3K/AKT Signaling Pathway

“…The role of epithelial cells in the pathogenesis of CRS has attracted more and more attention. As the first natural barrier to contact external stimuli and an important structure of innate immunity, epithelial cells on the surface of nasal mucosa play an important role in protecting the body from external harmful factors [10][11][12] . Once the epithelial cell barrier function is damaged, it is mainly manifested in epithelial cell abscission and dysfunction in CRS, which will provide conditions for the invasion of external harmful substances, such as bacteria, virus invasion and allergen exposure, so as to cause and aggravate the chronic inflammation of nasal cavity and paranasal sinus mucus membrane and lead to the accumulation of inflammatory cells and inflammatory factors [13,14] .…”