Abstract
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.
Highlights
Asthma is a chronic respiratory disease characterized by airway inflammation and heterogeneity in disease pathogenesis and severity, symptom triggers, and treatment responses
The clustering resulted in five asthma phenotypes (Figure 1): [1] asthma characterized by mixed eosinophilic and neutrophilic inflammation (Eos/Mix); [2] neutrophil-predominant asthma with low forced expiratory volume in 1 s (FEV1) (Neutro Low FEV); [3] biopsy neutrophil-predominant asthma with normal FEV1 (Neutro Normal FEV); [4] sputum neutrophilpredominant asthma with normal FEV1 (Neutro Normal FEV); [5] paucigranulocytic asthma (Pauci)
We found that patients with neutrophilic asthma and low FEV1 had the most interferonregulatory factor 5 (IRF5)+ macrophages of all asthma subgroups, which was significantly different from patients with mixed eosinophilic asthma and patients with neutrophilic asthma and normal FEV1 (Figure 2B)
Summary
Asthma is a chronic respiratory disease characterized by airway inflammation and heterogeneity in disease pathogenesis and severity, symptom triggers, and treatment responses. Cohort studies like UBIOPRED and SARP using clinical and transcriptomics data have shown the existence of different inflammatory subgroups (phenotypes) within asthma that are likely driven by different mechanistic pathways (endotypes) [1,2,3]. This variation within the disease has hampered current treatment of patients and the development of new treatment strategies [4]. No studies as of yet have addressed whether the different phenotypes of asthma associate with the presence of a specific macrophage subtype, while this may give more insight into the underlying disease mechanisms of each of these asthma phenotypes. As eosinophilic asthma is generally associated with Th2-high inflammation and neutrophilic asthma with Th1/Th17 inflammation [3, 22], we hypothesized that eosinophilic asthma would be characterized by having Th2-associated CD206+ macrophages, whereas neutrophilic asthma would have Th1/Th17-associated IRF5+ macrophages
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