IL-1α is critical for leukocyte recruitment during pulmonary Aspergillus fumigatus infection (MPF1P.776)

Abstract

Abstract Aspergillus fumigatus is a mold that causes severe pulmonary infections. Currently, our knowledge of how A. fumigatus growth is controlled in the respiratory tract is limited. Alveolar macrophages and the airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia; subsequently, neutrophils and macrophages are sequentially recruited to the respiratory tract to control fungal growth and germination. How neutrophils and macrophages are recruited to the respiratory tract after A. fumigatus infection remains ill defined. A. fumigatus instillation induced biphasic expression of the inflammasome-dependent cytokines IL-1β and IL-18 during the first 48 hours, while IL-1α expression linearly grew over the same period. Il1r1-deficient mice are highly susceptible to pulmonary A. fumigatus infection. Enhanced susceptibility of Il1r1-deficient mice correlated with defects in leukocyte recruitment and anti-fungal activity. Interestingly, IL-1α rather than IL-1β was crucial for optimal leukocyte recruitment. IL-1α signaling enhanced the production of CXCL1, which was responsible for pulmonary leukocyte recruitment. In contrast, the inflammasome and IL-1β was only essential for optimal activation of anti-fungal activity of leukocytes. As such, Pycard-deficient mice were only mildly susceptible to A. fumigatus infection. Taken together, our data reveal central, non-redundant roles for IL-1α and IL-1β in controlling A. fumigatus infection in the lung.