scholarly journals Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation

2021 ◽  
Vol 6 (56) ◽  
pp. eabb7221
Author(s):  
Daniel F. Dwyer ◽  
Jose Ordovas-Montanes ◽  
Samuel J. Allon ◽  
Kathleen M. Buchheit ◽  
Marko Vukovic ◽  
...  
Keyword(s):  
Mast Cells ◽  
Nasal Polyposis ◽  
Inflammatory Diseases ◽  
Severe Disease ◽  
Intermediate Phenotype ◽  
Airway Mucosa ◽  
Fibrotic Diseases ◽  
Type 2 Inflammation

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MCTC) and epithelial MCs expressing tryptase without chymase (MCT). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine–mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MCT and MCTC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38highCD117high MCs that is markedly expanded during T2 inflammation. These CD38highCD117high MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTC subsets. CD38highCD117high MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MCT–like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MCTC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.

Chronic rhinosinusitis with nasal polyposis (CRSwNP): the correlation between expression of Galectin-10 and Clinical-Cytological Grading (CCG)

2021 ◽  
pp. 194589242110498
Author(s):  
Matteo Gelardi ◽  
Giuseppe Stefano Netti ◽  
Rossana Giancaspro ◽  
Federica Spadaccino ◽  
Antonio Pennella ◽  
...  
Keyword(s):  
Mast Cells ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Nasal Polyposis ◽  
Inflammatory Cells ◽  
Eosinophilic Inflammation ◽  
Double Positive ◽  
Double Label ◽  
Type 2 Inflammation

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is typically characterized by Type 2 inflammation. Several biomarkers of eosinophilic inflammation, including Galectin-10, also known as Charcot-Leyden crystal protein (CLCP), have been identified to establish eosinophilic infiltration of polyps, a reliable predictor of recurrence. Objective: We aimed to evaluate the Galectin-10 expression in nasal polyps of patients with CRSwNP and to assess the correlation of Charcot-Leyden crystals expression to the severity of CRSwNP according to Clinical-Cytological Grading (CCG). Methods A double-label immunofluorescence was performed to evaluate the expression of Gal-10, CD15, Tryptase, and CD63 and their eventual co-localization on histological samples of 18 patients with CRSwNP. Double-positive Gal-10+CD15+ and Galectin-10+Tryptase+ inflammatory cells were counted by confocal microscopy. Results Galectin-10 was detectable in all examined tissues from CRSwNP patients, and its expression increased as low, medium and high CCG tissues were examined, respectively. Galectin-10 was extensively present in inflammatory cells, while limited Galectin-10 deposits were detected around mucosal epithelial cells. Conclusion We showed the strong correlation between CCG and Galectin-10 expression, mainly colocalized with infiltrating eosinophils and mast-cells, in patients affected by CRSwNP.

scholarly journals Differential Expression of TFF1 and TFF3 in Patients Suffering from Chronic Rhinosinusitis with Nasal Polyposis

2019 ◽  
Vol 20 (21) ◽  
pp. 5461 ◽  
Author(s):  
Martina Mihalj ◽  
Maro Bujak ◽  
Josip Butković ◽  
Željko Zubčić ◽  
Maja Tolušić Levak ◽  
...  
Keyword(s):  
Chronic Rhinosinusitis ◽  
Target Gene ◽  
Nasal Polyposis ◽  
Sinus Surgery ◽  
Mrna Levels ◽  
Nasal Turbinate ◽  
Family Factor ◽  
Nasal Septoplasty ◽  
Type 2 Inflammation

Trefoil family factor (TFF) proteins contribute to antimicrobial defense and the maintenance of sinonasal epithelial barrier integrity. Dysregulation of TFF expression may be involved in the development of chronic inflammation and tissue remodeling characteristically found in chronic rhinosinusitis with nasal polyposis (CRSwNP). Expressions of TFF1 and TFF3 were determined in specimens of middle nasal turbinate (MNT-0), bulla ethmoidalis (BE), and nasal polyps (NP) from CRSwNP patients (n = 29) and inferior nasal turbinate from a group of control patients (underwent nasal septoplasty, n = 25). An additional MNT sample was collected 6 months after functional endoscopic sinus surgery (FESS, MNT-6). TFF1 mRNA levels were significantly reduced in all specimens by approximately three- to five-fold, while TFF3 was increased in MNT-0, as compared with controls. Six months after surgery their levels were reversed to control values. CRSwNP patients with S. epidermidis isolated from sinus swabs showed upregulation of TFF3 in MNT and NP as compared with patients with sterile swabs. Target gene regulation was not affected by the presence of type 2 inflammation in patients with confirmed allergy. Results of this study imply participation of TFFs genes in the development of CRSwNP.

scholarly journals The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

2017 ◽  
Vol 31 (6) ◽  
pp. 345-351 ◽  
Author(s):  
Charlie Palmer ◽  
Jennifer K. Mulligan ◽  
Sarah E. Smith ◽  
Carl Atkinson
Keyword(s):  
Cytokine Production ◽  
Inflammatory Diseases ◽  
Upper Airway ◽  
Cell Types ◽  
Inflammatory Cytokine Production ◽  
And Function ◽  
Immunologic Profile ◽  
Type 2 Inflammation

Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are inflammatory diseases of the upper airway, with a similar immunologic profile, characterized by aberrant and persistent type 2 inflammation. One cell population that has been identified as altered in both disease types is regulatory T cell (Treg). Tregs have the capacity to modulate T-effector function and suppress inflammatory cytokine production in a broad range of cell types. Given the ability of Tregs to control inflammation, the role of Tregs in respiratory diseases has attracted much attention. As discussed in this article, alterations in the Treg numbers and function, or both, have been identified in AR and CRSwNP, although much of the data is conflicting. Here, we explored what is known and, in many cases, unknown about the mechanisms by which Tregs differentiate and function, and how these functions can be controlled in the mucosal microenvironment. By gaining a greater understanding of these processes, it may be possible to harness the natural immunosuppressive activity of Tregs to ameliorate the chronic inflammation associated with AR and CRSwNP.

scholarly journals Alternative splicing of interleukin-33 and type 2 inflammation in asthma

2016 ◽  
Vol 113 (31) ◽  
pp. 8765-8770 ◽  
Author(s):  
Erin D. Gordon ◽  
Laura J. Simpson ◽  
Cydney L. Rios ◽  
Lando Ringel ◽  
Marrah E. Lachowicz-Scroggins ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mast Cells ◽  
Airway Epithelial Cells ◽  
Full Length ◽  
Biologically Active ◽  
Target Cells ◽  
Interleukin 33 ◽  
Type 2 Inflammation

Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an “alarmin” during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.

scholarly journals The Fate of Activated Group 2 Innate Lymphoid Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Mathä ◽  
Itziar Martinez-Gonzalez ◽  
Catherine A. Steer ◽  
Fumio Takei
Keyword(s):  
Stromal Cells ◽  
Inflammatory Diseases ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
First Line ◽  
The Past ◽  
Mucosal Tissues ◽  
Group 2 ◽  
Type 2 Inflammation

Group 2 innate lymphoid cells (ILC2s) reside in both mucosal and non-mucosal tissues and play critical roles in the first line of defense against parasites and irritants such as allergens. Upon activation by cytokines released from epithelial and stromal cells during tissue damage or stimulation, ILC2s produce copious amounts of IL-5 and IL-13, leading to type 2 inflammation. Over the past 10 years, ILC2 involvement in a variety of human diseases has been unveiled. However, questions remain as to the fate of ILC2s after activation and how that might impact their role in chronic inflammatory diseases such as asthma and fibrosis. Here, we review studies that have revealed novel properties of post-activation ILC2s including the generation of immunological memory, exhausted-like phenotype, transdifferentiation and activation-induced migration.

scholarly journals Roles of IL-25 in Type 2 Inflammation and Autoimmune Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chong Deng ◽  
Na Peng ◽  
Yuan Tang ◽  
Na Yu ◽  
Cuicui Wang ◽  
...  
Keyword(s):  
Host Defense ◽  
Inflammatory Diseases ◽  
Sequence Similarity ◽  
Defense Responses ◽  
T Helper ◽  
Th 17 ◽  
Autoimmune Pathogenesis ◽  
Type 2 Inflammation ◽  
Inflammatory Effect

Interleukin-17E (IL-25) is a member of the IL-17 cytokine family that includes IL-17A to IL-17F. IL-17 family cytokines play a key role in host defense responses and inflammatory diseases. Compared with other IL-17 cytokine family members, IL-25 has relatively low sequence similarity to IL-17A and exhibits a distinct function from other IL-17 cytokines. IL-25 binds to its receptor composed of IL-17 receptor A (IL-17RA) and IL-17 receptor B (IL-17RB) for signal transduction. IL-25 has been implicated as a type 2 cytokine and can induce the production of IL-4, IL-5 and IL-13, which in turn inhibits the differentiation of T helper (Th) 17. In addition to its anti-inflammatory properties, IL-25 also exhibits a pro-inflammatory effect in the pathogenesis of Th17-dominated diseases. Here, we review recent advances in the roles of IL-25 in the pathogenesis of inflammation and autoimmune diseases.

Patient characteristics, biomarkers, and exacerbation risk in severe, uncontrolled asthma

2021 ◽  
pp. 2100413
Author(s):  
Monica Kraft ◽  
Guy Brusselle ◽  
J. Mark FitzGerald ◽  
Ian D. Pavord ◽  
Matthew Keith ◽  
...  
Keyword(s):  
Asthma Exacerbation ◽  
Clinical Characteristics ◽  
Nasal Polyposis ◽  
Blood Eosinophil ◽  
Uncontrolled Asthma ◽  
Asian Race ◽  
Exacerbation Risk ◽  
Type 2 Inflammation ◽  
Eosinophil Counts

BackgroundGreater precision in asthma exacerbation risk prediction may improve outcomes. We sought to identify clinical characteristics and biomarkers associated with elevated exacerbation risk in patients with severe, uncontrolled asthma.MethodsData were pooled from seven similarly designed Phase II and III randomized controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualized asthma exacerbation rates (AAERs) for patients randomized to placebo were assessed by baseline clinical characteristics and by biomarker concentrations at baseline and over the study duration.ResultsThe AAER for the 2016 patients in the combined placebo group was 0.91 (95% CI 0.84‒0.98). Baseline characteristics associated with greater AAER were frequent or severe exacerbations within the prior 12 months, nasal polyposis, maintenance oral corticosteroid use, Asian race, and Asian or Western European region. AAER increased with baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) concentration, with the greatest AAER occurring for patients with eosinophils ≥300 cells·μL−1 and FeNO ≥50 ppb. No relationship was observed between baseline serum immunoglobulin E concentration and AAER. Combining type 2 inflammation criteria for eosinophils and FeNO had greater prognostic value than either biomarker alone. Persistent eosinophil and FeNO elevations throughout the study period were associated with greater AAER.ConclusionsExacerbation history, maintenance corticosteroid use, nasal polyposis, Asian race, geographic region, and elevations in blood eosinophil counts and FeNO concentrations (particularly when combined and/or persistently achieving type 2 inflammation criteria) were associated with increased exacerbation risk in patients with severe, uncontrolled asthma.

scholarly journals Baseline Conservative and Surgical Management in the Treatment of NSAID-Exacerbated Respiratory Disease

2021 ◽  
Vol 2 ◽  
Author(s):  
Saara Sillanpää ◽  
Jura Numminen
Keyword(s):  
Respiratory Disease ◽  
Nasal Polyposis ◽  
Oral Corticosteroid ◽  
Medical Condition ◽  
Sinus Surgery ◽  
Chronic Medical Condition ◽  
Eosinophilic Inflammation ◽  
Type 2 Inflammation

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a chronic medical condition that includes asthma, chronic rhinosinusitis with nasal polyposis, and hypersensitivity to aspirin and other NSAIDs. Eosinophilic inflammation in the upper and lower airways is treated with local corticosteroids, repeated antibiotics, oral corticosteroid courses, endoscopic sinus surgery, and in some cases aspirin treatment after desensitization (ATAD). Nevertheless, the disease may be uncontrolled and it has a great impact on quality of life. A better understanding of the pathomechanisms of the disease and the development of medications that target type 2 inflammation mediators may have a crucial role in achieving better disease control in patients with N-ERD.

Sign in / Sign up

Export Citation Format

Share Document