Matrix Metalloproteinase-9-Dependent Release of IL-1β by Human Eosinophils

Abstract EN

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-1β 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-1β 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-1β protein into a mature, releasable, and active form.

We have demonstrated that eosinophils can release IL-1β 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-1β 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-1β 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-1β into a ~15 kDa form and allows the release of IL-1β from cytokine-activated eosinophils.

Therefore, we conclude that activated eosinophils produce MMP-9, which causes the release of IL-1β in an inflammasome/caspase-1-independent manner.

The production of IL-1β 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.