Abstract
Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines IL-1β and IL-18 within the first 12 hours, while IL-1α expression continually increases over at least the first 48 hours. Strikingly, Il1r1-deficient mice are highly susceptible to pulmonary A. fumigatus challenge exemplified by robust fungal proliferation in the lung parenchyma. Enhanced susceptibility of Il1r1-deficient mice correlated with defects in leukocyte recruitment and anti-fungal activity. Importantly, IL-1α rather than IL-1β was crucial for optimal leukocyte recruitment. IL-1α signaling enhanced the production of CXCL1. Moreover, CCR2+ monocytes are required for optimal early IL-1α and CXCL1 expression in the lungs, as selective depletion of these cells resulted in their diminished expression, which in turn regulated the early accumulation of neutrophils in the lung after A. fumigatus challenge. Enhancement of pulmonary neutrophil recruitment and anti-fungal activity by CXCL1 treatment could limit fungal growth in the absence of IL-1α signaling. In contrast to the role of IL-1α in neutrophil recruitment, the inflammasome and IL-1β were only essential for optimal activation of anti-fungal activity of macrophages. As such, Pycard-deficient mice are 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 murine lung.
Highlights
The mold Aspergillus fumigatus is one of the leading causes of invasive fungal infections
Our work demonstrates a central role for the cytokine IL-1α in orchestrating the optimal recruitment of neutrophils and monocytes, whereas IL-1β and the inflammasome are more important in activation of anti-fungal activity of the monocytes
Our studies indicate that CCR2+ monocytes are required for optimal production of IL-1α in the lungs of A. fumigatus challenged mice
Summary
The mold Aspergillus fumigatus is one of the leading causes of invasive fungal infections. It is the causative agent of severe pulmonary infections such as invasive pulmonary aspergillosis (IPA), a disease of high morbidity and mortality which affects immunocompromised individuals [1]. IPA has been a disease of growing concern over recent decades due to an increase in the immunocompromised population, caused by advances in immunosuppressive drugs and organ transplantation methods as well as chemotherapy treatments in cancer patients [2]. There is increasing evidence that IPA can sporadically develop in certain immunocompetent populations [3]. The recent emergence of drug resistance has further limited treatment options in certain clinical cases and geographic areas [5,6,7]
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