MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.

Publication Type:

Journal Article

Source:

Infection and immunity, Volume 76, Issue 3, p.952-8 (2008)

Keywords:

2008, Animals, Aspergillosis, Aspergillus fumigatus, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Center-Authored Paper, Clinical Research Division, Colony Count, Microbial, Comparative Medicine Core Facility, Cytokines, Experimental Histopathology Core Facility, INFLAMMATION, Killer Cells, Natural, lung, Macrophages, Alveolar, Male, MICE, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Necrosis, Neutrophils, Shared Resources

Abstract:

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.