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Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 10 May 2024 | Viewed by 9279

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Dr. Seung-Heon Shin

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Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
Interests: mucosal immunity; airway inflammation; epithelial cell biology; eosinophils; fungal infection
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue on “Chronic Rhinosinusitis: Aetiology, Immunology and Treatment” (https://www.mdpi.com/journal/ijms/special_issues/crs_Immun).

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. However, the pathophysiology of CRS is not fully understood, and it has limited treatment options with heterogeneous disease groups.

CRS had been considered an infectious disease, with the focus being placed on identifying the pathogenic microbial organisms. However, recent studies have suggested that CRS may be related to immune-mediated diseases, the involvement of which may cause the exacerbation of local inflammatory responses. CRS is classified as eosinophilic or non-eosinophilic CRS based on the dominant inflammatory cell types. CRS can also be divided into Th1-, Th2-, and Th17-dominant CRS based on the presence of lymphocyte effector cells in sinonasal mucosa. Many researchers have tried to determine the pathogenesis of CRS by identifying key chemical mediators or transcription factors and using various animal models. In this regard, many efforts are being made to elucidate the immunopathologic mechanism of CRS. Because the CRS is a sinonasal mucosal inflammatory disease, surgical treatment has limitations. Biologics are attracting attention as a new therapeutic strategy for CRS.

This Special Issue will focus on advances in the field of mucosal immunity and their impact on our understanding of the development of CRS and immunologic effects of biologics for the treatment of CRS. IJMS is a journal of molecular science, so pure clinical studies are not suitable, but biomolecular experimental studies are welcome.

Dr. Seung-Heon Shin
Guest Editor

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Keywords

innate immunity
adaptive immunity
protease
cytokine
inflammation
epithelial cells
fibroblasts
eosinophils
lymphocytes
biologics

Published Papers (10 papers)

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Research

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16 pages, 3879 KiB

Open AccessArticle

Retinoic Acid Treatment Mitigates PM2.5-Induced Type 2 Inflammation: Insights into Modulation of Innate Immune Responses

by Hyun-Joo Lee and Dong-Kyu Kim

Int. J. Mol. Sci. 2024, 25(7), 3856; https://doi.org/10.3390/ijms25073856 - 29 Mar 2024

Viewed by 500

Abstract

Some studies have demonstrated the effects of particulate matter (PM) on chronic rhinosinusitis with nasal polyps (CRSwNP) development, as well as the therapeutic role of retinoic acid (RA) in nasal polypogenesis. However, the immunologic effect of PM in innate lymphoid cells (ILCs) and the exact mechanism of the therapeutic effect of RA remain unclear. Therefore, the present study investigated the effects of fine-dust-induced inflammation in CRSwNP and the mechanisms of the therapeutic effect of RA. PM2.5 exposure exacerbated pathological damage in the nasal mucosa of mice with nasal polyps (NP) via upregulation of type 2 inflammation. Additionally, PM2.5 exposure increased the expression of type 2 cytokines and epithelial-cell-derived cytokines (IL-33 and IL-25) significantly, as well as the ILC populations in human-NP-derived epithelial cells (HNECs). Moreover, RA supplementation significantly increased the expression of ILCreg in Lin−CD45+CD127+ cells, which in turn increased the levels of the anti-inflammatory cytokine IL-10. The findings suggest that PM2.5 exposures could aggravate the CRSwNP type 2 inflammation, and RA treatment may ameliorate fine-dust-induced inflammation by modulating the innate immune response. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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22 pages, 4954 KiB

Open AccessArticle

Staphylococcus aureus Biofilm-Secreted Factors Cause Mucosal Damage, Mast Cell Infiltration, and Goblet Cell Hyperplasia in a Rat Rhinosinusitis Model

by Ghais Houtak, Roshan Nepal, George Bouras, Gohar Shaghayegh, Catherine Bennett, John Finnie, Kevin Fenix, Alkis James Psaltis, Peter-John Wormald and Sarah Vreugde

Int. J. Mol. Sci. 2024, 25(6), 3402; https://doi.org/10.3390/ijms25063402 - 17 Mar 2024

Viewed by 660

Abstract

Chronic rhinosinusitis (CRS) is an inflammatory condition of the sinonasal mucosa. Despite being a common health issue, the exact cause of CRS is yet to be understood. However, research suggests that Staphylococcus aureus, particularly in its biofilm form, is associated with the disease. This study aimed to investigate the impact of long-term exposure to secreted factors of Staphylococcus aureus biofilm (SABSFs), harvested from clinical isolates of non-CRS carrier and CRS patients, on the nasal mucosa in a rat model. Animals were randomised (n = 5/group) to receive daily intranasal instillations of 40 μL (200 μg/μL) SABSFs for 28 days or vehicle control. The sinonasal samples were analysed through histopathology and transcriptome profiling. The results showed that all three intervention groups displayed significant lymphocytic infiltration (p ≤ 0.05). However, only the SABSFs collected from the CRSwNP patient caused significant mucosal damage, mast cell infiltration, and goblet cell hyperplasia compared to the control. The transcriptomics results indicated that SABSFs significantly enriched multiple inflammatory pathways and showed distinct transcriptional expression differences between the control group and the SABSFs collected from CRS patients (p ≤ 0.05). Additionally, the SABSF challenges induced the expression of IgA and IgG but not IgE. This in vivo study indicates that long-term exposure to SABSFs leads to an inflammatory response in the nasal mucosa with increased severity for S. aureus isolated from a CRSwNP patient. Moreover, exposure to SABSFs does not induce local production of IgE. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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13 pages, 8757 KiB

Open AccessArticle

A Novel Model of Staphylococcus aureus-Induced Lymphoplasmacytic Rhinosinusitis in Rats

by William Murphy, Sha Liu, Karen Hon, John Finnie, George Spyro Bouras, Sholeh Feizi, Ghais Houtak, Gohar Shaghayegh, Erich Vyskocil, Peter-John Wormald, Sarah Vreugde and Alkis J. Psaltis

Int. J. Mol. Sci. 2024, 25(6), 3336; https://doi.org/10.3390/ijms25063336 - 15 Mar 2024

Viewed by 510

Abstract

Chronic rhinosinusitis (CRS) is characterized by sinonasal mucosal inflammation. Staphylococcus aureus (S. aureus) is associated with severe CRS phenotypes. Different animal models have been proposed to study the association of CRS and S. aureus. However, current animal models are expensive due to the use of large animals, have high barriers to ethics approval, or require invasive surgical intervention, necessitating a need for a model that can overcome these limitations. This study aimed at establishing a reliable and efficient rat lymphoplasmacytic inflammatory model for rhinosinusitis. Sprague Dawley rats received a daily intranasal application of 20 μL of saline, S. aureus CI-182 exoprotein (250 μg/mL), or exoprotein CI-182 in combination with S. aureus clinical isolate (CI-908 or CI-913) 10⁸ colony-forming unit (CFU)/mL. The rats’ sinuses were harvested at 1 and 2 weeks post-intervention. The CFU and histopathologic examination of inflammation were evaluated. S. aureus clinical isolates CI-908 or CI-913 in combination with the exoprotein (CI-182) had higher CFUs and caused persistently higher inflammation at both the 1 and 2-week post-intervention compared to the exoprotein and saline group. The observed inflammatory cell type was lymphoplasmacytic. This study provided evidence that the combination of a S. aureus exoprotein with S. aureus induces inflammation that persists for a minimum of two weeks post-intervention. This model is the first known animal model to create the lymphoplasmacytic inflammation subtype seen in CRS patients. This offers a cost-effective, accessible, non-invasive, and easy-to-replicate model to study the causes and treatment of such inflammation. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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12 pages, 1457 KiB

Open AccessArticle

An In Vitro Study Evaluating the Safety of Mesalazine on Human Nasoepithelial Cells

by William Murphy, Sha Liu, Shari Javadiyan, Erich Vyskocil, Sholeh Feizi, Claudio Callejas, Peter-John Wormald, Sarah Vreugde and Alkis J. Psaltis

Int. J. Mol. Sci. 2024, 25(5), 2796; https://doi.org/10.3390/ijms25052796 - 28 Feb 2024

Viewed by 601

Abstract

Chronic rhinosinusitis (CRS) is a disease characterised by the inflammation of the nasal and paranasal cavities. It is a widespread condition with considerable morbidity for patients. Current treatment for chronic rhinosinusitis consists of appropriate medical therapy followed by surgery in medically resistant patients. Although oral steroids are effective, they are associated with significant morbidity, and disease recurrence is common when discontinued. The development of additional steroid sparing therapies is therefore needed. Mesalazine is a commonly used therapeutic in inflammatory bowel disease, which shares a similar disease profile with chronic rhinosinusitis. This exploratory in vitro study aims to investigate whether mesalazine could be repurposed to a nasal wash, which is safe on human nasoepithelial cells, and retains its anti-inflammatory effects. CRS patients’ human nasal epithelial cells (HNECs) were collected. HNECs were grown at an air-liquid interface (ALIs) and in a monolayer and challenged with mesalazine or a non-medicated control. Transepithelial electrical resistance, paracellular permeability, and toxicity were measured to assess epithelial integrity and safety. The anti-inflammatory effects of mesalazine on the release of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-α) were analysed using human leukemia monocytic cell line (THP-1). mesalazine did not impact the barrier function of HNEC-ALIs and was not toxic when applied to HNECs or THP-1 cells at concentrations up to 20 mM. mesalazine at 0.5 and 1 mM concentrations significantly inhibited TNF-α release by THP-1 cells. mesalazine effectively decreases TNF-α secretion from THP-1 cells, indicating the possibility of its anti-inflammatory properties. The safety profile of mesalazine at doses up to 20 mM suggests that it is safe when applied topically on HNECs. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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13 pages, 1492 KiB

Open AccessArticle

Aspergillus Enhances Eosinophil and Neutrophil Extracellular DNA Trap Formation in Chronic Rhinosinusitis

by Seung-Heon Shin, Mi-Kyung Ye, Dong-Won Lee, Mi-Hyun Choi and Sang-Yen Geum

Int. J. Mol. Sci. 2023, 24(24), 17264; https://doi.org/10.3390/ijms242417264 - 08 Dec 2023

Viewed by 767

Abstract

Chronic rhinosinusitis (CRS) is characterized by inflammatory cell infiltration in the sinonasal mucosa. Eosinophil and neutrophil extracellular traps (EETs and NETs, respectively) are prominently found in CRS. This study aimed to investigate the effect of airborne fungi, Alternaria alternata and Aspergillus fumigatus, on EET and NET formation. Nasal epithelial cells, eosinophils, and neutrophils were isolated from eosinophilic CRS (ECRS), non-ECRS (NECRS), and healthy control. We determined eosinophil and neutrophil transepithelial migration after fungal treatment. We then determined the release of EETs and NETs by fungi using Sytox Green staining and determined the role of reactive oxygen species (ROS) using ROS inhibitors. We identified more abundant EETs and NETs in ECRS than in NECRS. A. alternata and A. fumigatus enhanced eosinophil and neutrophil transepithelial migration. A. fumigatus strongly induced EET and NET formation in CRS and, simultaneously, suppressed fungal metabolic activity. EET formation in CRS is associated with nicotinamide adenine dinucleotide phosphate (NADPH)–oxidase and NET formation with NADPH–oxidase and mitochondrial ROS. A. fumigatus, but not A. alternata, induced EET and NET formation, and peripheral blood eosinophils and neutrophils exhibited different immune responses against A. fumigatus following the inflammatory status of the host. Aspergillus-fumigatus-induced EET and NET formation plays a crucial role in CRS pathogenesis. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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Review

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18 pages, 1296 KiB

Open AccessReview

Olfactory Loss in Rhinosinusitis: Mechanisms of Loss and Recovery

by Agnès Dekeyser, Caroline Huart, Thomas Hummel and Valérie Hox

Int. J. Mol. Sci. 2024, 25(8), 4460; https://doi.org/10.3390/ijms25084460 - 18 Apr 2024

Viewed by 303

Abstract

Chronic rhinosinusitis (CRS) is a highly prevalent disease and up to 83% of CRS patients suffer from olfactory dysfunction (OD). Because OD is specifically seen in those CRS patients that present with a type 2 eosinophilic inflammation, it is believed that type 2 inflammatory mediators at the level of the olfactory epithelium are involved in the development of this olfactory loss. However, due to the difficulties in obtaining tissue from the olfactory epithelium, little is known about the true mechanisms of inflammatory OD. Thanks to the COVID-19 pandemic, interest in olfaction has been growing rapidly and several studies have been focusing on disease mechanisms of OD in inflammatory conditions. In this paper, we summarize the most recent data exploring the pathophysiological mechanisms underlying OD in CRS. We also review what is known about the potential capacity of olfactory recovery of the currently available treatments in those patients. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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29 pages, 2452 KiB

Open AccessReview

Chronic Rhinosinusitis—Microbiological Etiology, Potential Genetic Markers, and Diagnosis

by Michał Michalik and Beata Krawczyk

Int. J. Mol. Sci. 2024, 25(6), 3201; https://doi.org/10.3390/ijms25063201 - 11 Mar 2024

Viewed by 894

Abstract

Chronic rhinosinusitis (CRS) is a significant public health problem. Bacterial colonization and impaired mucociliary clearance play a significant role in the inflammatory process. Several inflammatory pathways and host defense elements are altered in CRS, which may contribute to observed differences in the microbiome. To date, researching CRS has been difficult due to limited access to the studied tissue and a lack of available biomarkers. Ongoing scientific research is increasingly based on simple and objective analytical methods, including sensors, detection with PCR, and sequencing. Future research on microbiota and human factors should also include genomics, transcriptomics, and metabolomics approaches. This report analyzes the changes that occur in the paranasal sinuses of people with acute and chronic rhinosinusitis, the composition of the microbiota, the human genetic markers that may shed light on the predisposition to CRS, and the advantages and disadvantages of classical and molecular diagnostic methods, as well as addressing the difficulties of sinusitis treatment. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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21 pages, 901 KiB

Open AccessReview

Airways Type-2 Related Disorders: Multiorgan, Systemic or Syndemic Disease?

by Francesco Giombi, Gian Marco Pace, Francesca Pirola, Michele Cerasuolo, Fabio Ferreli, Giuseppe Mercante, Giuseppe Spriano, Giorgio Walter Canonica, Enrico Heffler, Sebastian Ferri, Francesca Puggioni, Giovanni Paoletti and Luca Malvezzi

Int. J. Mol. Sci. 2024, 25(2), 730; https://doi.org/10.3390/ijms25020730 - 05 Jan 2024

Viewed by 1003

Abstract

Chronic rhinosinusitis (CRS) has recently undergone a significant paradigm shift, moving from a phenotypical classification towards an “endotype-based” definition that places more emphasis on clinical and therapeutic aspects. Similar to other airway diseases, like asthma, most cases of CRS in developed countries exhibit a dysregulated type-2 immune response and related cytokines. Consequently, the traditional distinction between upper and lower airways has been replaced by a “united airway” perspective. Additionally, type-2 related disorders extend beyond respiratory boundaries, encompassing conditions beyond the airways, such as atopic dermatitis. This necessitates a multidisciplinary approach. Moreover, consideration of possible systemic implications is crucial, particularly in relation to sleep-related breathing diseases like Obstructive Sleep Apnoea Syndrome (OSAS) and the alteration of systemic inflammatory mediators such as nitric oxide. The trends in epidemiological, economic, and social burden are progressively increasing worldwide, indicating syndemic characteristics. In light of these insights, this narrative review aims to present the latest evidence on respiratory type-2 related disorders, with a specific focus on CRS while promoting a comprehensive perspective on the “united airways”. It also introduces a novel concept: viewing these conditions as a multiorgan, systemic, and syndemic disease. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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22 pages, 1977 KiB

Open AccessReview

Unraveling the Role of Epithelial Cells in the Development of Chronic Rhinosinusitis

by Jong-Gyun Ha and Hyung-Ju Cho

Int. J. Mol. Sci. 2023, 24(18), 14229; https://doi.org/10.3390/ijms241814229 - 18 Sep 2023

Cited by 1 | Viewed by 1473

Abstract

The pathophysiology of CRS is multifactorial and complex yet needs to be completed. Recent evidence emphasizes the crucial part played by epithelial cells in the development of CRS. The epithelial cells act as physical barriers and play crucial roles in host defense, including initiating and shaping innate and adaptive immune responses. This review aims to present a comprehensive understanding of the significance of nasal epithelial cells in CRS. New research suggests that epithelial dysfunction plays a role in developing CRS through multiple mechanisms. This refers to issues with a weakened barrier function, disrupted mucociliary clearance, and irregular immune responses. When the epithelial barrier is compromised, it can lead to the passage of pathogens and allergens, triggering inflammation in the body. Furthermore, impaired mucociliary clearance can accumulate pathogens and secretions of inflammatory mediators, promoting chronic inflammation. Epithelial cells can release cytokines and chemokines, which attract and activate immune cells. This can result in an imbalanced immune response that continues to cause inflammation. The interaction between nasal epithelial cells and various immune cells leads to the production of cytokines and chemokines, which can either increase or decrease inflammation. By comprehending the role of epithelial cells in CRS, we can enhance our understanding of the disease’s pathogenesis and explore new therapeutics. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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20 pages, 1293 KiB

Open AccessReview

Targeting Epithelium Dysfunction and Impaired Nasal Biofilms to Treat Immunological, Functional, and Structural Abnormalities of Chronic Rhinosinusitis

by Konstantinos Petalas, John Goudakos and George N. Konstantinou

Int. J. Mol. Sci. 2023, 24(15), 12379; https://doi.org/10.3390/ijms241512379 - 03 Aug 2023

Cited by 1 | Viewed by 1589

Abstract

Chronic rhinosinusitis (CRS) with (CRSwNP) or without (CRSsNP) nasal polyps is a prevalent and heterogeneous disorder existing as a spectrum of clinical conditions with complex underlying pathomechanisms. CRS comprises a broad syndrome characterized by multiple immunological features involving complex interactions between the genes, the microbiome, host- and microbiota-derived exosomes, the epithelial barrier, and environmental and micromilieu exposures. The main pathophysiological feature is an epithelial barrier disruption, accompanied by microbiome alterations and unpredictable and multifactorial immunologic overreactions. Extrinsic pathogens and irritants interact with multiple epithelial receptors, which show distinct expression patterns, activate numerous signaling pathways, and lead to diverse antipathogen responses. CRSsNP is mainly characterized by fibrosis and mild inflammation and is often associated with Th1 or Th17 immunological profiles. CRSwNP appears to be associated with moderate or severe type 2 (T2) or Th2 eosinophilic inflammation. The diagnosis is based on clinical, endoscopic, and imaging findings. Possible CRS biomarkers from the peripheral blood, nasal secretions, tissue biopsies, and nasally exhaled air are studied to subgroup different CRS endotypes. The primary goal of CRS management is to maintain clinical control by nasal douching with isotonic or hypertonic saline solutions, administration of nasal and systemic steroids, antibiotics, biologic agents, or, in persistent and more severe cases, appropriate surgical procedures. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 2.0)

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