title: IL-1α signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge.
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.
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Alayna K
authors: AK
authors: Caffrey
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Margaret M
authors: MM
authors: Lehmann
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Julianne M
authors: JM
authors: Zickovich
authors: Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America.
authors: Vanessa
authors: V
authors: Espinosa
authors: Geisel School of Medicine at Dartmouth, Department of Microbiology & Immunology, Hanover, New Hampshire, United States of America.
authors: Kelly M
authors: KM
authors: Shepardson
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Christopher P
authors: CP
authors: Watschke
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Kimberly M
authors: KM
authors: Hilmer
authors: Geisel School of Medicine at Dartmouth, Department of Microbiology & Immunology, Hanover, New Hampshire, United States of America.
authors: Arsa
authors: A
authors: Thammahong
authors: TGen North, Pathogen Genomics Research Division, Flagstaff, Arizona, United States of America.
authors: Bridget M
authors: BM
authors: Barker
authors: Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America.
authors: Amariliz
authors: A
authors: Rivera
authors: Geisel School of Medicine at Dartmouth, Department of Microbiology & Immunology, Hanover, New Hampshire, United States of America.
authors: Robert A
authors: RA
authors: Cramer
authors: Montana State University, Department of Immunology & Infectious Diseases, Bozeman, Montana, United States of America.
authors: Joshua J
authors: JJ
authors: Obar
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology*; D001985:Bronchial Provocation Tests; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D053582:Interleukin-1alpha / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055732:Pulmonary Aspergillosis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D053582:Interleukin-1alpha
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