A GM-CSF/IL-33 Pathway Facilitates Allergic Airway Responses to Sub-Threshold House Dust Mite Exposure

Abstract

Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen

“…Increased levels of GM-CSF amplifies the risk of allergic sensitization by lowering the threshold of allergen required for allergic responses 16 . Additionally, neutralizing GM-CSF at sensitization reduces allergic inflammation to HDM and Blomia tropicalis mite allergen 15,17,18 .…”

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

“…RAGE is highly expressed on type I alveolar epithelial cells (41–43), while IL-33 localizes to nuclei and is released by type II alveolar epithelial cells in response to damage (49–51). How RAGE activation might direct increased IL-33 expression is unclear, but it is known that type I and type II alveolar epithelial cells communicate through multiple paracrine and juxtacrine signaling pathways (52–55).…”

Pathogenic CD4 + T cells in patients with asthma

“…GM-CSF can also condition the airways to respond to lower doses of allergen through a pathway involving IL-33 secretion by alveolar type II cells. 68 In asthmatic patients, bronchial epithelial cells overexpress GM-CSF. 69 However, GM-CSF has also been linked to neutrophilic asthma, which lacks a prominent T H 2 signature, thereby questioning its role in T H 2-driven disease in human subjects.…”