American journal of respiratory cell and molecular biology | 2019
The Innate Immune Protein S100A9 Protects from Th2-Mediated Allergic Airway Inflammation.
Abstract
Calprotectin is a heterodimer of the proteins S100A8 and S100A9 and is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient S100A9-/- and wild-type C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen Alternaria alternata (Alt Ext) or PBS every third day over 9 days. On day 10, bronchoalveolar lavage fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of wild-type mice. Compared to wild-type mice, S100A9-/- mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, S100A9-/- mice accumulated significantly more IL-13+IL-5+CD4+ Th2 cells. S100A9-/- mice also accumulated a significantly lower proportion of CD4+ T regulatory cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced wild-type T regulatory cell suppressive activity in vitro. Therefore, this study identifies a role for the innate immune protein S100A9 in protection from CD4+ Th2 hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4+ T regulatory cell function.