Caffrey Alayna K, Lehmann Margaret M, Zickovich Julianne M, Espinosa Vanessa, Shepardson Kelly M, Watschke Christopher P, Hilmer Kimberly M, Thammahong Arsa, Barker Bridget M, Rivera Amariliz, Cramer Robert A, Obar Joshua J
Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America.
PLoS Pathog. 2015 Jan 28;11(1):e1004625. doi: 10.1371/journal.ppat.1004625. eCollection 2015 Jan.
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.
烟曲霉是一种可引发严重肺部感染的霉菌。我们对烟曲霉在呼吸道中生长如何受到控制的了解正在不断发展，但仍较为有限。肺泡巨噬细胞、肺驻留巨噬细胞和气道上皮细胞构成了抵御吸入烟曲霉分生孢子的第一道防线。随后，中性粒细胞和炎性CCR2⁺单核细胞被招募至呼吸道以阻止真菌生长。然而，烟曲霉暴露后中性粒细胞和巨噬细胞被招募至呼吸道的机制仍是一个正在研究的领域。在此我们表明，烟曲霉肺部攻击在最初12小时内诱导炎性小体依赖性细胞因子IL-1β和IL-18的表达，而IL-1α的表达至少在最初48小时内持续增加。引人注目的是，Il1r1基因缺陷小鼠对肺部烟曲霉攻击高度易感，表现为肺实质中真菌大量增殖。Il1r1基因缺陷小鼠易感性增强与白细胞招募和抗真菌活性缺陷相关。重要的是，IL-1α而非IL-1β对于最佳白细胞招募至关重要。IL-1α信号增强了CXCL1的产生。此外，CCR2⁺单核细胞对于肺部最佳早期IL-1α和CXCL1表达是必需的，因为选择性清除这些细胞会导致它们的表达减少，这反过来又调节了烟曲霉攻击后肺部中性粒细胞的早期积聚。在缺乏IL-1α信号的情况下，通过CXCL1处理增强肺部中性粒细胞招募和抗真菌活性可限制真菌生长。与IL-1α在中性粒细胞招募中的作用相反，炎性小体和IL-1β仅对巨噬细胞抗真菌活性的最佳激活至关重要。因此，Pycard基因缺陷小鼠对烟曲霉感染轻度易感。综上所述，我们的数据揭示了IL-1α和IL-1β在控制小鼠肺部烟曲霉感染中核心的、非冗余的作用。
