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Updated: Jun 6, 2025
Analysis of Pulmonary Dendritic Cell Maturation and Migration during Allergic Airway Inflammation
Published on: July 23, 2012
Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore
Emma L Houlder1, Sara Gago2, George Vere3
1Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom; Leiden University Center for Infectious Disease, Leiden University Medical Centre, Leiden, The Netherlands.
Background:
Exposure to fungi, especially Aspergillus fumigatus, can elicit potent allergic inflammation that triggers and worsens asthmatic disease. Dendritic cells (DCs) initiate allergic inflammatory responses to allergic stimuli. However, it is unclear if Af spores during isotropic growth (early spore swelling) can activate DCs to initiate allergic responses or if germination is required. This lack of basic understanding of how Af causes disease is a barrier to developing new treatments.
Objective:
We sought to show that a precise Af morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process.
Methods:
We used an Af strain deficient in pyrimidine biosynthesis (ΔpyrG) to generate populations of Af spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow-derived DCs (BMDCs), and their activation was measured via flow cytometry and ELISA to examine which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways to assess if they were able to mediate allergic inflammation in naïve recipient mice. Allergic airway inflammation in vivo was determined via flow cytometry, ELISA, and real-time quantitative PCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and in vivo allergic inflammation upon adoptive transfer.
Results:
We found that Af isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time-arrested Af stages, we found that at least 3 hours in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation in vivo. Incubation of germinating Af with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit in vivo allergic airway inflammation.
Conclusion:
Our results have pinpointed the precise stage of Af development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics partially reduced the potential of Af spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help prevent the development of fungal allergy.
Insights
Early swelling of Aspergillus fumigatus (Af) spores, not germination, activates dendritic cells (DCs) to cause allergic airway inflammation. Antifungal drugs partially reduce this Af-induced allergic response.
Area of Science:
- Mycology
- Immunology
- Allergy Research
Background:
- Exposure to Aspergillus fumigatus (Af) fungi triggers allergic inflammation and asthma.
- Dendritic cells (DCs) initiate allergic responses, but the role of Af spore development stages in DC activation is unclear.
- Understanding Af pathogenesis is crucial for developing new anti-asthma treatments.
Purpose of the Study:
- To determine if specific Af morphotypes during spore swelling activate DCs.
- To investigate if antifungal therapeutics can inhibit Af-induced allergic responses.
Main Methods:
- Generated Af spores arrested at various isotropic growth stages using nutrient manipulation.
- Assessed bone marrow-derived dendritic cell (BMDC) activation via flow cytometry and ELISA.
- Adoptively transferred activated BMDCs into mice to evaluate allergic airway inflammation in vivo.
- Tested the efficacy of itraconazole in inhibiting spore swelling, BMDC activation, and allergic inflammation.
Main Results:
- Isotropic growth of Af spores is essential for triggering BMDC activation and allergic airway inflammation.
- At least 3 hours of growth allowed spores to swell sufficiently to activate BMDCs.
- Itraconazole treatment reduced spore swelling and partially inhibited BMDC activation and subsequent allergic inflammation.
Conclusions:
- Identified the critical Af developmental stage (isotropic growth) that activates DCs, leading to allergic airway inflammation.
- Demonstrated that antifungal therapeutics can partially suppress Af-induced allergic responses, suggesting a mechanism for preventing fungal allergy.
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