SiglecF+ neutrophils: a door to treating air pollution-induced asthma exacerbations?

Published: October 12, 2021

Air pollution is a growing global threat to public health, particularly respiratory health. Currently, the most common chronic airway disease is asthma. Epidemiological studies show that the prevalence and incidence of asthma are closely linked to air pollution. However, preclinical studies show that air pollutants cannot by themselves induce the cardinal features of asthma, namely, airway hyperresponsiveness and type 2 inflammation. Rather, they act to strongly exacerbate asthma that has already been triggered by allergens. Since blocking these effects with new therapeutics could help ameliorate asthma or prevent asthma exacerbations, it is important to elucidate the underlying cellular and molecular mechanisms.

In a recent paper published in The Journal of Allergy and Clinical Immunology (JACI), Shin and colleagues showed for the first time that diesel exhaust particulate (DEP), a traffic-related air pollutant, not only induces emphysema (lung damage), but it also provokes the lungs to produce a novel type of neutrophil, namely, neutrophils that express the eosinophil marker SiglecF. While neutrophils promote health by destroying microorganisms, their ability to produce large amounts of immune factors and cell-toxic molecules means they can also sometimes cause disease. To determine how DEP causes SiglecF-expressing neutrophils to emerge and whether these cells can exacerbate asthma, Shin et al. exposed the lungs of mice to DEP and then subjected the lung immune cells to flow cytometry, transcriptome analysis, and in vivo and in vitro functional experiments. Later, they also examined whether blood samples from asthma patients contain neutrophils that express Siglec8, the human counterpart of murine SiglecF.

SiglecF+ neutrophils are unique in that they only emerge when the lungs are exposed to DEP: they do not arise in other models of lung disease, including asthma. They also differ from eosinophils and other SiglecF-expressing lung cells (alveolar macrophages) in terms of their morphology and transcription patterns. DEP induces their formation by damaging lung cells and causing them to leak ATP, a danger signal. The ATP then activates the P2X1 receptor on conventional neutrophils that reside in the lung, which in turn causes them to newly express SiglecF. This expression of SiglecF by lung neutrophils associates with their acquisition of two new characteristics, namely, much higher production of both cysteinyl leukotriene (CysLT) and neutrophil extracellular traps (NETs). CysLT is a pro-inflammatory lipid mediator that induces allergic disease: indeed, Shin et al. showed that SiglecF+ neutrophil-derived CysLTs alone could exacerbate the airway hyperresponsiveness and type 2 inflammation in asthmatic mice. NETs are web-like structures that permit neutrophils to kill microorganisms: Shin et al. showed that the NETs formed by SiglecF+ neutrophils are responsible for DEP-induced emphysema and provoke both type 2 and 3 immune responses. Notably, blocking both CysLTs and NETs profoundly alleviated DEP-induced asthma exacerbations. Shin et al. then showed that patients with severe asthma have more CysLT- and NET-associated Siglec8+ neutrophils in their blood than healthy control subjects and patients with mild asthma.

In summary, Shin and colleagues showed that SiglecF+/Siglec8+ neutrophils play an important pathogenic role in air pollutant-induced asthma exacerbations. Targeting Siglec8+ neutrophils in asthma patients or blocking CysLTs and NETs could be an effective therapeutic alternative for patients with uncontrolled and steroid-resistant asthma. Since SiglecF/Siglec8 is a well-known marker of eosinophils, this study also reveals the limitations of the current dichotomous classification of asthma into eosinophilic and neutrophilic asthma. It thus suggests that further investigations into neutrophil heterogeneity will broaden our current understanding of refractory pulmonary diseases.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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