Alternaria-derived serine protease activity drives IL-33–mediated asthma exacerbations

Abstract

BackgroundThe fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear.ObjectiveWe sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation.MethodsIL-33 levels were quantified in wild-type and ST2−/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later.ResultsAlternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model.ConclusionAlternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease.

A Novel CD4+ T Cell–Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology

“…ILC2 cells have been shown to be prolific producers of type II cytokines in response to both pulmonary and intradermal HDM exposure (48,49). Similarly, murine models of fungal allergen exposure to Alternaria have also demonstrated a role for ILC2 cells as cytokine producers (50,51). In the present PC model, ILC2 cells appeared to have a greater function in maintaining the optimal Th2 response as opposed to directly contributing to pathology via cytokine production.…”

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

“…The fact that AERD often occurs in nonatopic hosts (16), some of whom nevertheless show significantly increased total serum IgE (17) and all of whom display marked eosinophilic tissue inflammation, suggests that the disease involves immune mechanisms that are distinct from allergen-specific adaptive type 2 immune responses. Whereas IL-33 is released as an alarmin from necrotic cells (35), it is also released in a controlled manner from epithelial cells in response to danger signals from viruses (36), fungi (37), and helminths (38). IL-33 acts at the IL-1 receptor-like protein ST2 to activate both myeloid and lymphoid innate effector cells, resulting in the production of cytokines (IL-5, IL-13, IL-9) that drive eosinophil-rich pathology, either independently of adaptive immunity (39,40), or in concert with conventional allergen-driven Th2 responses (41).…”

<b>Increases in IL-33 production by fimbriae and lipopeptide from </b><i><b>Porphyromonas gingivalis</b></i><b> in mouse bone marrow-derived dendritic cells via Toll-like receptor </b><b>2 </b>

“…PAMPs, proteinases, and proinflammatory cytokines (12,13,21,22). In this study, we demonstrated that P. gingivalis induced IL-33 expression in mouse BMDCs.…”

“…In contrast, abundant evidence suggests that IL-33 is also involved in the development of chronic inflammatory diseases such as arthritis (25). IL-33 is induced in response to such fungal allergens as Alternaria infection, ragweed pollen, and proinflammatory cytokines, and it induces the production of Th2 cytokines by group 2 innate lymphoid cells, for the initiation of allergic inflammation in response to pathogens (12,13,21,22). USA).…”