| Autor: |
Esnault S; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Kelly EA; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Johnson SH; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., DeLain LP; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Haedt MJ; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Noll AL; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Sandbo N; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA., Jarjour NN; University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA. |
| Abstrakt: |
Asthma is often associated with airway eosinophilia, and therapies targeting eosinophils are now available to treat severe eosinophilic asthma. Eosinophilic asthma is often due to a type-2 immune response and production of IL-5, which leads to eosinophilopiesis and recruitment of mature eosinophils in the airways. A concomitant type-2 and type-17 response has been reported in some individuals. IL-17 may be enhanced by IL-1 β production and can lead to neutrophilic inflammation. In fact, both eosinophilic and neutrophilic (mixed granulocytic) inflammation are simultaneously present in a large population of patients with asthma. In monocyte/macrophage cell populations, release of mature IL-1 β occurs via toll-like receptor ligand-induced activation of the inflammasome. Within the inflammasome, a cascade of events leads to the activation of caspase-1, which cleaves pro-IL-1 β protein into a mature, releasable, and active form. We have demonstrated that eosinophils can release IL-1 β in a Toll-like receptor ligand-independent fashion. The objective of this study was to determine the mechanisms underlying the production and maturation of IL-1 β in cytokine-activated eosinophils. Using eosinophils from circulating blood and from bronchoalveolar lavage fluid after an airway allergen challenge, the present study demonstrates that cytokine-activated eosinophils express and release a bioactive form of IL-1 β with an apparent size less than the typical 17 kDa mature form produced by macrophages. Using a zymography approach and pharmacological inhibitors, we identified matrix metalloproteinase-9 (MMP-9) as a protease that cleaves pro-IL-1 β into a ~15 kDa form and allows the release of IL-1 β from cytokine-activated eosinophils. Therefore, we conclude that activated eosinophils produce MMP-9, which causes the release of IL-1 β in an inflammasome/caspase-1-independent manner. The production of IL-1 β by eosinophils may be a link between the eosinophilic/type-2 immune response and the neutrophilic/type-17 immune response that is often associated with a more severe and treatment-refractory type of asthma. |
