Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop

• Published in: The Journal of immunology (1950) Vol. 185; no. 10; pp. 6190 - 6197
• Main Authors: Park, Stacy J, Burdick, Marie D, Brix, William K, Stoler, Mark H, Askew, David S, Strieter, Robert M, Mehrad, Borna
• Format: Journal Article
• Language: English
• Published: United States 15.11.2010
• Subjects: Animals; Aspergillus; Aspergillus - immunology; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - immunology; Chemokine CCL20 - biosynthesis; Chemokine CCL20 - immunology; Chemokines - biosynthesis; Chemokines - immunology; Chemotaxis, Leukocyte - immunology; Cytokines - biosynthesis; Cytokines - immunology; Dendritic Cells - immunology; Lung - immunology; Lung - microbiology; Mice; Mice, Transgenic; Neutropenia - complications; Neutropenia - immunology; Pulmonary Aspergillosis - complications; Pulmonary Aspergillosis - immunology; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002064

Current understanding of specific defense mechanisms in the context of neutropenic infections is limited. It has previously been reported that invasive aspergillosis, a prototypic opportunistic infection in neutropenic hosts, is associated with marked accumulation of inflammatory dendritic cells (DCs) in the lungs. Given recent data indicating that neutrophils can modulate immune responses independent of their direct microbial killing, we hypothesized that neutropenia impacts the host response to Aspergillus by determining the migration and phenotype of lung DCs. Inflammatory DCs, but not other DC subsets, were found to accumulate in the lungs of neutropenic hosts challenged with killed or live-attenuated Aspergillus as compared with nonneutropenic hosts, indicating that the accumulation was independent of neutrophil microbicidal activity. The mechanism of this accumulation in neutropenic hosts was found to be augmented influx of DCs, or their precursors, from the blood to the lungs. This effect was attributable to greatly elevated lung TNF expression in neutropenic as compared with nonneutropenic animals. This resulted in greater lung expression of the chemokine ligands CCL2 and CCL20, which, in turn, mediated enhanced recruitment of TNF-producing inflammatory DCs, resulting in a positive feedback cycle. Finally, in the context of neutropenic invasive aspergillosis, depletion of DCs resulted in impaired fungal clearance, indicating that this mechanism is protective for the host. These observations identify what we believe is a novel defense mechanism in invasive aspergillosis that is the result of alterations in DC traffic and phenotype and is specific to neutropenic hosts.