Recognition of Fungal Protease Activities Induces Cellular Activation and Eosinophil-Derived Neurotoxin Release in Human Eosinophils
| Autor: | Yoshinori Matsuwaki, Kota Wada, James L. Checkel, Linda M. Benson, Christopher B. Lawrence, Jens U. Ponikau, Kyoko Hotta, M. Cristine Charlesworth, Thomas A. White, Hirohito Kita, Yoshinari Inoue |
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| Rok vydání: | 2009 |
| Předmět: |
Proteases
Fungal protein Protease Innate immune system medicine.medical_treatment Immunology Eosinophil-derived neurotoxin Eosinophil Biology biology.organism_classification Alternaria alternata Microbiology medicine.anatomical_structure otorhinolaryngologic diseases medicine Immunology and Allergy Eosinophil degranulation |
| Zdroj: | The Journal of Immunology. 183:6708-6716 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0901220 |
| Popis: | Eosinophils are multifunctional leukocytes implicated in the pathogenesis of asthma and in immunity to certain organisms. Associations between exposure to an environmental fungus, such as Alternaria, and asthma have been recognized clinically. Protease-activated receptors (PARs) are G protein-coupled receptors that are cleaved and activated by serine proteases, but their roles in innate immunity remain unknown. We previously found that human eosinophils respond vigorously to Alternaria organisms and to the secretory product(s) of Alternaria with eosinophils releasing their proinflammatory mediators. In this study, we investigated the roles of protease(s) produced by Alternaria and of PARs expressed on eosinophils in their immune responses against fungal organisms. We found that Alternaria alternata produces aspartate protease(s) and that human peripheral blood eosinophils degranulate in response to the cell-free extract of A. alternata. Eosinophils showed an increased intracellular calcium concentration in response to Alternaria that was desensitized by peptide and protease ligands for PAR-2 and inhibited by a PAR-2 antagonistic peptide. Alternaria-derived aspartate protease(s) cleaved PAR-2 to expose neo-ligands; these neo-ligands activated eosinophil degranulation in the absence of proteases. Finally, treatment of Alternaria extract with aspartate protease inhibitors, which are conventionally used for HIV-1 and other microbes, attenuated the eosinophils’ responses to Alternaria. Thus, fungal aspartate protease and eosinophil PAR-2 appear critical for the eosinophils’ innate immune response to certain fungi, suggesting a novel mechanism for pathologic inflammation in asthma and for host-pathogen interaction. |
| Databáze: | OpenAIRE |
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