Eosinophils in the Pathogenesis of Paediatric Severe Asthma
The lung is a site where eosinophils are rare in health, but accumulation is a characteristic of allergic disease. The importance of eosinophil location and the specific tissue that they are within in determining their effector function has been highlighted by data linking eosinophils within adipose tissue with glucose homeostasis and the metabolic syndrome. Eosinophils present within healthy adipose tissue helped maintain metabolic homeostasis and glucose tolerance through the interaction with and regulation of the activity of alternatively activated macrophages in the fat, which was supported by ILC2s. This suggests that the location of eosinophils within different tissues might influence their function and may shed light on their pathological function in asthma, particularly in patients who are overweight. In relation to this, an oral hypoglycaemic agent, metformin, which reverses obesity-associated insulin resistance, has been shown to reduce allergen-induced eosinophilic inflammation in obese mice. Treatment with metformin only reduced eosinophil accumulation within lung tissue, suggesting metformin may facilitate cell migration into the airway lumen, thus accelerating clearance of tissue eosinophilia in obese mice. In a similar manner, only submucosal tissue eosinophils (within the airway wall) have a relationship with BMI in adults with severe asthma, whereas sputum (representing airway lumen) or peripheral blood eosinophil counts had no relationship with BMI. Thus, suggesting lung tissue eosinophils may be functionally more important than those released into the airway lumen. Interestingly, a similar finding has been reported in children whereby obesity was not associated with either sputum or peripheral blood eosinophilia. Although this was interpreted as a lack of association between asthma, obesity and inflammation by the authors, it may simply be that an association between mucosal eosinophils and obesity was missed since the patients did not undergo bronchial biopsy. Another study in children has shown similar blood levels of eosinophils in asthmatic obese and non-obese patients, but increased eosinophil activity, demonstrated by spontaneous chemotaxis, in the asthmatic obese patients compared with asthmatic non-obese patients.
In summary, these data demonstrating a role for eosinophils within adipose tissue in glucose and metabolic homeostasis, and a pathological role for eosinophils when in specific tissue sites (such as the lung), have started to shed some light on their role in health, but also in driving disease in allergic asthma. It is becoming increasingly apparent that therapies that target tissue-specific eosinophils may be more effective than those that only reduce peripheral or airway luminal eosinophilia, and this seems especially important in the context of severe disease and obesity-associated disease. It may be that the steroid-resistant eosinophilia that is in paediatric severe asthma is mediated predominantly by eosinophils within the lung tissue, and mechanisms that aim to investigate the interactions between tissue eosinophils and lung structural cells, such as the bronchial epithelium or airway smooth muscle, are an important avenue to pursue.
Tissue-Specific Eosinophils, Obesity and the Metabolic Syndrome
The lung is a site where eosinophils are rare in health, but accumulation is a characteristic of allergic disease. The importance of eosinophil location and the specific tissue that they are within in determining their effector function has been highlighted by data linking eosinophils within adipose tissue with glucose homeostasis and the metabolic syndrome. Eosinophils present within healthy adipose tissue helped maintain metabolic homeostasis and glucose tolerance through the interaction with and regulation of the activity of alternatively activated macrophages in the fat, which was supported by ILC2s. This suggests that the location of eosinophils within different tissues might influence their function and may shed light on their pathological function in asthma, particularly in patients who are overweight. In relation to this, an oral hypoglycaemic agent, metformin, which reverses obesity-associated insulin resistance, has been shown to reduce allergen-induced eosinophilic inflammation in obese mice. Treatment with metformin only reduced eosinophil accumulation within lung tissue, suggesting metformin may facilitate cell migration into the airway lumen, thus accelerating clearance of tissue eosinophilia in obese mice. In a similar manner, only submucosal tissue eosinophils (within the airway wall) have a relationship with BMI in adults with severe asthma, whereas sputum (representing airway lumen) or peripheral blood eosinophil counts had no relationship with BMI. Thus, suggesting lung tissue eosinophils may be functionally more important than those released into the airway lumen. Interestingly, a similar finding has been reported in children whereby obesity was not associated with either sputum or peripheral blood eosinophilia. Although this was interpreted as a lack of association between asthma, obesity and inflammation by the authors, it may simply be that an association between mucosal eosinophils and obesity was missed since the patients did not undergo bronchial biopsy. Another study in children has shown similar blood levels of eosinophils in asthmatic obese and non-obese patients, but increased eosinophil activity, demonstrated by spontaneous chemotaxis, in the asthmatic obese patients compared with asthmatic non-obese patients.
In summary, these data demonstrating a role for eosinophils within adipose tissue in glucose and metabolic homeostasis, and a pathological role for eosinophils when in specific tissue sites (such as the lung), have started to shed some light on their role in health, but also in driving disease in allergic asthma. It is becoming increasingly apparent that therapies that target tissue-specific eosinophils may be more effective than those that only reduce peripheral or airway luminal eosinophilia, and this seems especially important in the context of severe disease and obesity-associated disease. It may be that the steroid-resistant eosinophilia that is in paediatric severe asthma is mediated predominantly by eosinophils within the lung tissue, and mechanisms that aim to investigate the interactions between tissue eosinophils and lung structural cells, such as the bronchial epithelium or airway smooth muscle, are an important avenue to pursue.