MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.
Toll-like receptors and the beta-glucan receptor, dectin-1, mediate macrophage inflammatory responses to Aspergillus fumigatus through MyD88-dependent and -independent signaling mechanisms; however, pulmonary inflammatory responses in MyD88-deficient mice challenged with A. fumigatus are poorly defined. The role of MyD88 signaling in early pulmonary inflammation and fungal clearance was evaluated in C57BL/6J wild-type (WT) and MyD88-deficient (MyD88-/-) mice. Early (<48 h) after infection, MyD88-/- mice had higher fungal burdens than those of WT mice, although fungal burdens rapidly declined (>72 h) in both. MyD88-/- mice had less consolidated inflammation, with fewer NK cells, in lung tissue early (24 h) after infection than did WT mice. At the latter time point, MyD88-/- mouse lungs were characterized by a large amount of necrotic cellular debris and fibrin, while WT lungs had organized inflammation. Although there were equivalent numbers of macrophages in WT and MyD88-/- mouse lung tissues, MyD88-/- cells demonstrated delayed uptake of green fluorescent protein-expressing A. fumigatus (GFP-Af293); histologically, MyD88-/- mouse lungs had more hyphal invasion of terminal airways and vessels, the appearance of bronchiolar epithelial cell necrosis, and necrotizing vasculitis. MyD88-/- lung homogenates contained comparatively decreased amounts of interleukin-1beta (IL-1beta), IL-6, KC, and gamma interferon and paradoxically increased amounts of tumor necrosis factor alpha and macrophage inflammatory protein 1alpha. These data indicate that the MyD88-dependent pathway mediates acute pulmonary fungal clearance, inflammation, and tissue injury very early after infection. Resolution of abnormalities within a 3-day window demonstrates the importance of redundant signaling pathways in mediating pulmonary inflammatory responses to fungi.
Bretz
Camille
C
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Gersuk
Geoff
G
Knoblaugh
Sue
S
Chaudhary
Neelkamal
N
Randolph-Habecker
Julie
J
Hackman
Robert C
RC
Staab
Janet
J
Marr
Kieren A
KA
D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D007249:Inflammation / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000737:chemistry / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D009336:Necrosis / Q000473:pathology; D009504:Neutrophils / Q000276:immunology
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88