Neutrophilic Asthma Is Associated With Smoking, High Numbers of IRF5+, and Low Numbers of IL10+ Macrophages

Asthma is a heterogenous disease with different inflammatory subgroups that differ in disease severity. This disease variation is hampering treatment and development of new treatment strategies. Macrophages may contribute to asthma phenotypes by their ability to activate in different ways, i.e., T helper cell 1 (Th1)-associated, Th2-associated, or anti-inflammatory activation. It is currently unknown if these different types of activation correspond with specific inflammatory subgroups of asthma. We hypothesized that eosinophilic asthma would be characterized by having Th2-associated macrophages, whereas neutrophilic asthma would have Th1-associated macrophages and both having few anti-inflammatory macrophages. We quantified macrophage subsets in bronchial biopsies of asthma patients using interferon regulatory factor 5 (IRF5)/CD68 for Th1-associated macrophages, CD206/CD68 for Th2-associated macrophages and interleukin 10 (IL10)/CD68 for anti-inflammatory macrophages. Macrophage subset percentages were investigated in subgroups of asthma as defined by unsupervised clustering using neutrophil/eosinophil counts in sputum and tissue and forced expiratory volume in 1 s (FEV1). Asthma patients clustered into four subgroups: mixed-eosinophilic/neutrophilic, paucigranulocytic, neutrophilic with normal FEV1, and neutrophilic with low FEV1, the latter group consisting mainly of smokers. No differences were found for CD206+ macrophages within asthma subgroups. In contrast, IRF5+ macrophages were significantly higher and IL10+ macrophages lower in neutrophilic asthmatics with low FEV1 as compared to those with neutrophilic asthma and normal FEV1 or mixed-eosinophilic asthma. This study shows that neutrophilic asthma with low FEV1 is associated with high numbers of IRF5+, and low numbers of IL10+ macrophages, which may be the result of combined effects of smoking and having asthma.

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Management of the patient with eosinophilic asthma: a new era begins

ERJ Open Research ◽

10.1183/23120541.00024-2015 ◽

2015 ◽

Vol 1 (1) ◽

pp. 00024-2015 ◽

Cited By ~ 55

Author(s):

Jantina C. de Groot ◽

Anneke ten Brinke ◽

Elisabeth H.D. Bel

Keyword(s):

Inhaled Corticosteroids ◽

Late Onset ◽

Airflow Obstruction ◽

Poor Quality ◽

Eosinophilic Asthma ◽

New Era ◽

Systemic Corticosteroids ◽

Asthma Patients ◽

Oral Corticosteroids ◽

Bronchial Biopsies

Now that it is generally accepted that asthma is a heterogeneous condition, phenotyping of asthma patients has become a mandatory part of the diagnostic workup of all patients who do not respond satisfactorily to standard therapy with inhaled corticosteroids. Late-onset eosinophilic asthma is currently one of the most well-defined asthma phenotypes and seems to have a different underlying pathobiology to classical childhood-onset, allergic asthma. Patients with this phenotype can be identified in the clinic by typical symptoms (few allergies and dyspnoea on exertion), typical lung function abnormalities (“fixed” airflow obstruction, reduced forced vital capacity and increased residual volume), typical comorbidities (nasal polyposis) and a good response to systemic corticosteroids. The definitive diagnosis is based on evidence of eosinophilia in bronchial biopsies or induced sputum, which can be estimated with reasonable accuracy by eosinophilia in peripheral blood. Until recently, patients with eosinophilic asthma had a very poor quality of life and many suffered from frequent severe exacerbations or were dependent on oral corticosteroids. Now, for the first time, novel biologicals targeting the eosinophil have become available that have been shown to be able to provide full control of this type of refractory asthma, and to become a safe and efficacious substitute for oral corticosteroids.

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Heterogeneous Response of Airway Eosinophilia to Anti-IL-5 Biologics in Severe Asthma Patients

Journal of Personalized Medicine ◽

10.3390/jpm12010070 ◽

2022 ◽

Vol 12 (1) ◽

pp. 70

Author(s):

Maruša Kopač Šokić ◽

Matija Rijavec ◽

Peter Korošec ◽

Urška Bidovec-Stojkovič ◽

Izidor Kern ◽

...

Keyword(s):

Treatment Strategies ◽

Eosinophilic Inflammation ◽

Asthma Control Test ◽

Sputum Induction ◽

Immunological Parameters ◽

Eosinophilic Asthma ◽

Interleukin 5 ◽

Severe Eosinophilic Asthma ◽

Asthma Patients

Many questions concerning responders (R) and nonresponders (NR) in severe eosinophilic asthma (SEA) after blocking the IL-5 (interleukin 5) pathway are still not clear, especially regarding the early parameters of response to biologics in personalized treatment strategies. We evaluated 17 SEA patients treated with anti-IL-5 biologics (16 patients mepolizumab, one patient benralizumab) before the introduction of biologics, and at a week 16 follow-up. Clinical, cellular and immunological parameters in peripheral blood were measured in R and NR. Sputum induction with the measurement of cellular and immunological parameters was performed at 16 weeks only. There were 12 R and 5 NR to biologics. After 16 weeks, there was a significant improvement in percentages of FEV1 (p = 0.001), and asthma control test (ACT) (p = 0.001) in the R group, but not in NR. After 16 weeks, the eosinophils in induced sputum were 27.0% in NR and 4.5% in R (p = 0.05), with no difference in IL-5 concentrations (p = 0.743). Peripheral eosinophilia decreased significantly in NR (p = 0.032) and R (p = 0.002). In patients with SEA on anti-IL-5 therapy, there was a marked difference in airway eosinophilic inflammation between R and NR already at 16 weeks, after anti-IL-5 introduction.

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Stratification of eosinophilic asthma patients treated with reslizumab and GINA Step 4 or 5 therapy

ERJ Open Research ◽

10.1183/23120541.00004-2017 ◽

2017 ◽

Vol 3 (3) ◽

pp. 00004-2017 ◽

Cited By ~ 11

Author(s):

Guy Brusselle ◽

Janice Canvin ◽

Sivan Weiss ◽

Shawn X. Sun ◽

Roland Buhl

Keyword(s):

Lung Function ◽

Patient Reported Outcomes ◽

Secondary Analysis ◽

Forced Expiratory Volume ◽

Phase Iii ◽

Eosinophilic Asthma ◽

Interleukin 5 ◽

Severe Eosinophilic Asthma ◽

Patient Reported ◽

Asthma Patients

Reslizumab, an anti-interleukin-5 monoclonal antibody, significantly reduces exacerbation frequency and improves lung function, asthma control and quality of life in adults with severe eosinophilic asthma, as demonstrated in Phase III studies.This secondary analysis assessed reslizumab's efficacy in patients receiving baseline treatment per Global Initiative for Asthma (GINA) Step 4 and Step 5 guidelines.Pooled data from duplicate, Phase III, reslizumab versus placebo studies in patients with severe eosinophilic asthma (blood eosinophils ≥400 cells·µL−1) were stratified by baseline therapy. Efficacy assessments were exacerbation rates and changes from baseline forced expiratory volume in 1 s (FEV1) and patient-reported outcomes.Of 953 patients, 69% (n=657) and 11% (n=106) were receiving Step 4 and Step 5 therapy, respectively. Compared with placebo, reslizumab reduced exacerbation rates by 53% (95% CI 0.36–0.62) and 72% (95% CI 0.15–0.52), in Step 4 and Step 5 groups respectively. By study end, reslizumab increased FEV1 in Step 4 and Step 5 groups by 103 mL (95% CI 52–154 mL) and 237 mL (95% CI 68–407 mL), respectively. Reslizumab also improved patient-reported outcomes compared with placebo in both groups.Reslizumab reduces exacerbation rates and improves lung function and patient-reported outcomes in patients with eosinophilic asthma receiving therapy per Steps 4 and 5 of the GINA guidelines.

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Anti-Inflammatory and Antioxidant Properties of Carvacrol and Magnolol, in Periodontal Disease and Diabetes Mellitus

Molecules ◽

10.3390/molecules26226899 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6899

Author(s):

Georgiana Cicalău ◽

Petru Babes ◽

Horia Calniceanu ◽

Adelina Popa ◽

Gabriela Ciavoi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Periodontal Disease ◽

Antioxidant Properties ◽

Treatment Strategies ◽

Stem Bark ◽

Potential Benefits ◽

Therapeutic Properties ◽

Anti Inflammatory ◽

New Treatment ◽

Magnolia Officinalis

Periodontal disease and diabetes mellitus are two pathologies that are extremely widespread worldwide and share the feature of chronic inflammation. Carvacrol is a phenolic monoterpenoid, produced by a variety of herbs, the most well-known of which is Origanum vulgare. Magnolol is a traditional polyphenolic compound isolated from the stem bark of Magnolia officinalis, mainly used in Chinese medicine. The purpose of this paper is to review the therapeutic properties of these bioactive compounds, in the treatment of periodontitis and diabetes. Based on our search strategy we conducted a literature search in the PubMed and Google Scholar databases to identify studies. A total of one hundred eighty-four papers were included in the current review. The results show that carvacrol and magnolol have anti-inflammatory, antioxidant, antimicrobial, anti-osteoclastic, and anti-diabetic properties that benefit both pathologies. Knowledge of the multiple activities of carvacrol and magnolol can assist with the development of new treatment strategies, and the design of clinical animal and human trials will maximize the potential benefits of these extracts in subjects suffering from periodontitis or diabetes.

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IL-10–producing macrophages preferentially clear early apoptotic cells

Blood ◽

10.1182/blood-2005-10-4144 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4930-4937 ◽

Cited By ~ 147

Author(s):

Wei Xu ◽

Anja Roos ◽

Nicole Schlagwein ◽

Andrea M. Woltman ◽

Mohamed R. Daha ◽

...

Keyword(s):

Interleukin 10 ◽

Apoptotic Cells ◽

Gm Csf ◽

Inflammatory Status ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Anti Inflammatory ◽

Macrophage Colony ◽

Macrophage Subset ◽

Factor Α

AbstractEfficient clearance of apoptotic cells seems to be a prerequisite to prevent the development of autoimmunity. Here we identify that macrophage colony-stimulating factor (M-CSF)–driven macrophages (Mø2s) are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells. This macrophage subset has intrinsic anti-inflammatory properties, characterized by high interleukin-10 (IL-10) production in the absence of proinflammatory cytokines, such as IL-6 and tumor necrosis factor-α (TNF-α). Importantly, whereas the IL-6 and TNF-α production by granulocyte-macrophage (GM)–CSF–driven macrophages (Mø1s) is inhibited upon uptake of apoptotic cells, the anti-inflammatory status of Mø2 is retained during phagocytosis. Mø2s were shown to use CD14 to tether apoptotic cells, whereas recognition of phosphatidylserine (PS) contributed to uptake of early apoptotic cells. Mø2s showed more potent macropinocytosis compared with dendritic cells (DCs) and Mø1s, and uptake of apoptotic cells was inhibited by a macropinocytosis inhibitor. Our studies suggest that, under steady-state conditions, IL-10–producing Mø2s are prominently involved in the clearance of early apoptotic cells.

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