The term “eosinophilic” asthma (EA) generally refers to the clinical inflammatory phenotype of asthma wherein a significant number of sputum, airway, and/or blood eosinophils are present. Conversely, individuals with “noneosinophilic” asthma (NEA) may still demonstrate low numbers of eosinophils, but the dominant inflammatory cell type may include neutrophils, mixed granulocyte inflammatory cells, or very few inflammatory cells, termed paucigranulocytic inflammation. Although the mechanisms driving EA are becoming clearer, by contrast much less attention has been given to the underlying mechanisms that drive NEA, leading to a lack of available therapies for this patient population. Although “phenotype” refers to the observable characteristics of disease in an individual, by “endotypes” we mean the specific biological mechanism that causes those observed properties of any given phenotype. Understanding the manifold mechanisms or endotypes contributing to EA and NEA and the resulting clinical phenotypes derived from these endotypes will lead to novel treatment options and provide an opportunity for more precise and tailored treatments. This review highlights the mechanisms currently believed to underlie the recognized subphenotypes of EA and NEA and briefly discusses their clinical presentations as well as implications for treatment. Definition of Eosinophilic and Noneosinophilic Asthma

/pdf/eosinophilic-and-noneosinophilic-asthma-3q3mikamn1.pdf

Eosinophilic and Noneosinophilic Asthma

Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis. In addition to neutrophil extracellular traps (NETs), enucleated neutrophil cytoplasts were evident in the lungs. Surprisingly, allergen-driven airway neutrophilia was decreased in peptidyl arginine deiminase 4-deficient mice with defective NETosis but not by deoxyribonuclease treatment, implicating the cytoplasts for the non-type 2 immune responses to allergen. Neutrophil cytoplasts were also present in mediastinal lymph nodes, and the cytoplasts activated lung dendritic cells in vitro to trigger antigen-specific interleukin-17 (IL-17) production from naive CD4+ T cells. Bronchoalveolar lavage fluid from patients with severe asthma and high neutrophil counts had detectable NETs and cytoplasts that were positively correlated with IL-17 levels. Together, these translational findings have identified neutrophil cytoplast formation in asthmatic lung inflammation and linked the cytoplasts to T helper 17-mediated neutrophilic inflammation in severe asthma.

/pdf/neutrophil-cytoplasts-induce-th17-differentiation-and-skew-1qop9od45e.pdf

Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma.

Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.

https://www.mdpi.com/1422-0067/19/12/4090/pdf

How Glucocorticoids Affect the Neutrophil Life

Liproxstatin-1 alleviates LPS/IL-13-induced bronchial epithelial cell injury and neutrophilic asthma in mice by inhibiting ferroptosis.

Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide, imposing a great burden on the healthcare system. Regrettably, effective CKD therapeutic strategies are yet available due to their elusive pathogenic mechanisms. CKD is featured by progressive inflammation and fibrosis associated with immune cell dysfunction, leading to the formation of an inflammatory microenvironment, which ultimately exacerbating renal fibrosis. Transforming growth factor β1 (TGF-β1) is an indispensable immunoregulator promoting CKD progression by controlling the activation, proliferation, and apoptosis of immunocytes via both canonical and non-canonical pathways. More importantly, recent studies have uncovered a new mechanism of TGF-β1 for de novo generation of myofibroblast via macrophage-myofibroblast transition (MMT). This review will update the versatile roles of TGF-β signaling in the dynamics of renal immunity, a better understanding may facilitate the discovery of novel therapeutic strategies against CKD.

/pdf/tgf-b1-signaling-immune-dynamics-of-chronic-kidney-diseases-12iqb3sdw6.pdf

TGF-β1 Signaling: Immune Dynamics of Chronic Kidney Diseases

BACKGROUND Innate immunity has been thought to be involved in asthma pathogenesis. Pentraxins, acting as soluble pattern recognition molecules, play an important role in humoral innate immunity. Asthma is a heterogeneous inflammatory disease of airways and can be classified as eosinophilic or non-eosinophilic asthma. OBJECTIVE To investigate whether pentraxin levels differ in subjects with eosinophilic versus non-eosinophilic asthma. Furthermore, to access the predictive performance of pentraxin levels for discriminating asthma inflammatory phenotypes. METHODS A total of 80 asthmatic patients and 24 healthy control subjects underwent sputum induction at study inclusion. Differential leucocyte counts were performed on selected sputum. Plasma C-reactive protein (CRP), serum amyloid P (SAP), pentraxin 3 (PTX3), and sputum SAP, PTX3, IL-8 levels were determined by enzyme-linked immunosorbent assay. RESULTS Subjects with non-eosinophilic asthma had significantly increased pentraxin levels compared with those with eosinophilic asthma and healthy controls, with median (interquartile range) plasma CRP levels of 0.86 (0.28-2.07), 0.26 (0.14-0.85), and 0.15 (0.09-0.45)mg/L (P < .001), respectively, plasma SAP levels of 33.69 (19.79-58.39), 19.76 (16.11-30.58), and 20.06 (15.68-31.11)mg/L (P = .003), respectively, and sputum PTX3 levels of 4.9 (1.35-18.72), 0.87 (0.30-2.07), and 1.08 (0.31-4.32)ng/mL (P < .001), respectively. Conversely, sputum SAP concentrations of eosinophilic asthmatics (median, 21.49 ng/mL; IQR, 6.86-38.79 ng/mL) were significantly higher than those of non-eosinophilic patients (median, 8.15 ng/mL; IQR, 2.82-18.01 ng/mL) and healthy controls (median, 8.79 ng/mL; IQR, 2.00-16.18 ng/mL). Asthma patients with high plasma CRP (P = .004), SAP (P = .005) and sputum PTX3 levels (P < 0.001) also had significantly lower sputum eosinophil percentages. Sputum PTX3 levels had the best power (11.18-fold, P < .001) to predict non-eosinophilic airway inflammation in asthma patients. CONCLUSION AND CLINICAL RELEVANCE Pentraxin levels differed significantly between patients with non-eosinophilic asthma and those with eosinophilic asthma. Furthermore, elevated pentraxin expressions may predict non-eosinophilic airway inflammation in asthmatic patients.

Pentraxin levels in non-eosinophilic versus eosinophilic asthma.

The Buffering Role of Self-compassion in the Association Between Loneliness with Depressive Symptoms: A Cross-Sectional Survey Study Among Older Adults Living in Residential Care Homes During COVID-19

Abstract 
 Objective:
 Club cell 10-kDa protein (CC10) is a documented biomarker for airway obstructive diseases. Primarily produced by nonciliated club cells in the distal airway and in nasal epithelial cells, CC10 suppresses Th2 cell differentiation and Th2 cytokine production. In this study, we aimed to determine whether CC10 can also be used as an alternative biomarker for identifying Type 2 (T2) asthma. 
 Methods:
 74 patients with asthma, and 24 healthy controls were enrolled in the study. T2-high asthma was defined as elevation in two or more biomarkers, such as sputum eosinophilia ≥ 3%, high blood eosinophils ≥ 300/µL, or high FeNO ≥ 30 ppb. T2-low asthma was defined as no elevation in biomarkers. Enzyme-linked immunosorbent assay (ELISA) was used to assess the CC10 levels in plasma. 
 Results:
 The plasma CC10 level in patients with T2-high asthma was lower than that of patients with T2-low asthma and healthy controls (P < 0.05). To distinguish between T2-high and T2-low phenotype in patients with asthma, a receiver-operating characteristic (ROC) analysis was performed. It showed a sensitivity of 58.1% and specificity of 78.0% when using 22.74 ng/ml of plasma CC10. Correlation analysis indicated that the plasma CC10 level was inversely correlated with sputum eosinophil, blood eosinophil, and FeNO, and positively correlated with log PD20. However, no correlation with sputum neutrophil percentages, macrophage percentages, IgE, or lung function was found. 
 Conclusions:
 Plasma CC10 is potentially useful in predicting T2-high and T2-low asthma. Lower plasma CC10 was associated with enhanced airway hyperresponsiveness, and Type 2 inflammation.

Club cell 10-kDa protein (CC10) as a surrogate for identifying type 2 asthma phenotypes

The effectiveness of corticosteroids (GCs) varies greatly in interstitial lung diseases (ILDs). In this study, we aimed to compare the gene expression profiles of patients with cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF), and non-specific interstitial pneumonia (NSIP) and identify the molecules and pathways responsible for GCs sensitivity in ILDs. Three datasets (GSE21411, GSE47460, and GSE32537) were selected. Differentially expressed genes (DEGs) among COP, IPF, NSIP, and healthy control (CTRL) groups were identified. Functional enrichment analysis and protein-protein interaction network analysis were performed to examine the potential functions of DEGs. There were 128 DEGs when COP versus CTRL, 257 DEGs when IPF versus CTRL, 205 DEGs when NSIP versus CTRL, and 270 DEGs when COP versus IPF. The DEGs in different ILDs groups were mainly enriched in the inflammatory response. Further pathway analysis showed that "interleukin (IL)-17 signaling pathway" (hsa04657) and "tumor necrosis factor (TNF) signaling pathway" were associated with different types of ILDs. A total of 10 genes associated with inflammatory response were identified as hub genes and their expression levels in the IPF group were higher than those in the COP group. Finally, we identified two GCs' response-related differently expressed genes (FOSL1 and DDIT4). Our bioinformatics analysis demonstrated that the inflammatory response played a pathogenic role in the progression of ILDs. We also illustrated that the inflammatory reaction was more severe in the IPF group compared to the COP group and identified two GCs' response-related differently expressed genes (FOSL1 and DDIT4) in ILDs. 

Genetic Programs Between Steroid-Sensitive and Steroid-Insensitive Interstitial Lung Disease

Licari and colleagues detected plasma pentraxin 3 (PTX3) and serum Ddimer levels, and reported significant elevated concentrations for both biomarkers in asthmatic patients compared with healthy controls, but neither was observed to be associated with clinical parameters. Elevated PTX3 expressions in asthmatic airways were firstly observed by Zhang et al.,1 and the same group reported that PTX3 deletion enhanced airway inflammation, mucus production and airway hyperresponsiveness in an ovalbumininduced asthma model through a TH17dominant phenotype.2 Indeed, before this, PTX3 had been widely studied and reported to play essential nonredundant roles in innate immunity, inflammation, matrix deposition and female fertility, and was secreted by many cell types and induced by various different stimuli.3 The functional versatility and various cellular source of PTX3 suggest that its concentrations, particularly at systemic level, are influenced by a multitude of factors, which may partly explain the inconsistencies of PTX3 levels in previous studies, especially with relatively small sample size. On the other hand, extensive evidence indicates coagulation and anticoagulation disturbance and increased risk of pulmonary thromboembolism in asthmatic patients,4-7 but altered coagulation pathways do not play a central role in the pathogenesis of asthma on the basis of current understanding. Accordingly, both PTX3 and Ddimer levels have limited predictive value for clinical characteristics of asthma. In view of the limited and discordant evidence, we also do not think PTX3 and Ddimer can be useful biomarkers for asthma severity, control and management, consistent with the authors’ perspective. Indeed, PTX3 and Ddimer are important indicators of innate immune activation and fibrinolytic activity, respectively, but their roles in asthma may not limit to this. Given that asthma is a heterogeneous disease, with different underlying pathological processes, we consider differences in PTX3 and Ddimer expression in asthma patients may mainly reflect asthma endotype rather than its phenotype, and further studies are still needed to explore the mechanisms. ORCID

PTX3 and D-dimer in children with asthma: A real-world study-Reply.

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