Abstract
Asthma is an inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, and bronchial hyper-responsiveness. House dust mites (HDM) are the most prevalent cause of allergic sensitization. Canonical and noncanonical inflammasomes are multiprotein complexes that assemble in response to pathogen or danger-associated molecular patterns (PAMPs or DAMPs). Murine caspase-11 engages the noncanonical inflammasome. We addressed the role of caspase-11 in mediating host responses to HDM and subsequent allergic inflammation using caspase-11-/- mice, which lack caspase-11 while express caspase-1. We found that HDM induce caspase-11 expression in vitro. The presence of IL-4 and IL-13 promote caspase-11 expression. Additionally, caspase-11-/- macrophages show reduced release of IL-6, IL-12, and KC, and express lower levels of costimulatory molecules (e.g., CD40, CD86 and MHCII) in response to HDM stimulation. Notably, HDM sensitization of caspase-11-/- mice resulted in similar levels of IgE responses and hypothermia in response to nasal HDM challenge compared to WT. However, analysis of cell numbers and cytokines in bronchiolar alveolar lavage fluid (BALF) and histopathology of representative lung segments demonstrate altered inflammatory responses and reduced neutrophilia in the airways of the caspase-11-/- mice. These findings indicate that caspase-11 regulates airway inflammation in response to HDM exposure.
Highlights
Asthma is a long-term recurring inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, chronic airway inflammation and bronchial hyper-responsiveness (Platts-Mills and Chapman 1987, Arlian and Platts-Mills 2001, Thomas 2012)
There is a strong correlation between the level of House dust mites (HDM) exposure and sensitization, which is a strong predictor for asthma (Birrell, Van Oosterhout et al 2010, De Alba, Raemdonck et al 2010)
We used caspase-11−/− mice and macrophages from these mice to dissect whether caspase-11 plays a regulatory role in HDM induced allergic inflammation
Summary
Asthma is a long-term recurring inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, chronic airway inflammation and bronchial hyper-responsiveness (Platts-Mills and Chapman 1987, Arlian and Platts-Mills 2001, Thomas 2012). Different forms of asthma can coexist in some patients including atopic (allergic, Th2-dependent), and non-atopic (non-allergic, Th2-independent) forms These forms are initiated and regulated by multiple genetic and environmental factors, such as HDM allergens. Proteases-dependent effect of mite allergens is associated with breaching the epithelial layer, breaking tight junctions and stimulating protease-activated receptors. These events lead to increased epithelium permeability and production of chemokines and cytokines, which recruits antigen presenting cells (APCs) into the epithelial layers, promoting airway inflammation and remodelling (Asokananthan, Graham et al 2002, Kato, Takai et al 2009, Jacquet 2011, Jacquet 2011, Kubo 2017). Even though CD4+ Th2 cells orchestrate the HDM allergic response via production of IgE against mite allergens, promoting inflammation and lung remodelling (Na, Cho et al 2016), it is recognized that the innate immune system plays a fundamental role in initiating and shaping the allergic response by programming and maintaining Th2-biased adaptive immunity in response to HDM allergens and their contaminants (Hammad, Chieppa et al 2009, Willart and Lambrecht 2009)
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