Abstract
Future precision medicine requires further clarifying the mechanisms of inflammation in the severe endotypes of chronic airway diseases such as asthma and chronic rhinosinusitis (CRS). The presence of neutrophils in the airways is often associated with severe airway inflammation, while their precise contribution to the severe inflammation is largely unknown. We aimed to study the role of neutrophils in BALB/c and C57BL/6 mice exposed to Alternaria alternata (Alt). The mice were exposed to Alt extract for twelve hours or ten days to induce allergic airway inflammation. C57BL/6 mice exposed to Alt responded with eosinophilic infiltration and the characteristic IL-5 upregulation. In contrast, the inflammatory response to Alt extract in BALB/c mice was characterized by a neutrophilic response, high levels of G-CSF, and elastase in the lungs. The lack of neutrophils affected the processing of IL-33 in BALB/c mice, as was demonstrated by depletion of neutrophils through intraperitoneal injections of anti-Ly6G antibody. Our data identifies the key role of neutrophils in airway inflammation through IL-33 cleavage in the Alt-induced airway inflammation in mice, which could potentially underline the different endotypes in human disease.
Highlights
Severe asthma and chronic rhinosinusitis (CRS) with nasal polyps remain the most severe and often uncontrolled extremes of type 2 inflammatory diseases of the upper and lower airways [1, 2]
The bronchiolar lavage fluid (BALF) of C57BL/6 mice mostly contained eosinophils (Figure 1C), while BALB/c mice responded with a neutrophilia (Figure 1D)
The neutrophilic inflammation in BALB/c was accompanied by an upregulation of G-CSF (Figure 1E) in the lungs 12 hours after the Alt treatment, consistent with the function of G-CSF in promoting the recruitment of neutrophils from the bone marrow after airway allergen challenge [27, 28]
Summary
Severe asthma and chronic rhinosinusitis (CRS) with nasal polyps remain the most severe and often uncontrolled extremes of type 2 inflammatory diseases of the upper and lower airways [1, 2]. Type 2 inflammatory responses are characterized by the production of cytokines, such as IL-4, IL-5, and IL13, secreted by classic Th2 cells; and by innate immune cells, such as group 2 innate lymphoid cells (ILC2s), basophils, eosinophils, and mast cells. The proteolytic cleavage of IL-33 in its activation domain results in the generation of shorter “mature” forms of IL-33 that are at least 10-30 fold more potent than full-length IL-33 in the induction of type 2 inflammation and activation of ILC2s and Th2 cells [19,20,21]. We hypothesized that neutrophils might play an important role in the regulation of IL-33 activity, which may contribute to a better understanding of the regulation of inflammation in severe airway disease. To study the relative contribution of neutrophils, anti-Ly6G neutralizing antibodies causing neutrophil depletion were injected into the mice, and inflammatory parameters along with cytokine profile were studied
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