The Nucleotide-Binding Domain, Leucine-Rich Repeat Protein 3 Inflammasome/IL-1 Receptor I Axis Mediates Innate, but Not Adaptive, Immune Responses after Exposure to Particulate Matter under 10 μm

Abstract

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. Inhaled PM induces innate immune responses by airway epithelial cells that may lead to the exacerbation or de novo development of airway disease. We have previously shown that 10-μm PM (PM10) activates the nucleotide-binding domain, leucine-rich repeat protein (NLRP) 3 inflammasome in human airway epithelial cells. Our objective was to determine the innate and adaptive immune responses mediated by the airway epithelium NLRP3 inflammasome in response to PM10 exposure. Using in vitro cultures of human airway epithelial cells and in vivo studies with wild-type and Nlrp3(-/-) mice, we investigated the downstream consequences of PM10-induced NLPR3 inflammasome activation on cytokine production, cellular inflammation, dendritic cell activation, and PM10-facilitated allergic sensitization. PM10 activates an NLRP3 inflammasome/IL-1 receptor I (IL-1RI) axis in airway epithelial cells, resulting in IL-1β, CC chemokine ligand-20, and granulocyte/macrophage colony-stimulating factor production, which is associated with dendritic cell activation and lung neutrophilia. Despite these profound innate immune responses in the airway epithelium, the NLRP3 inflammasome/IL-1RI axis is dispensable for PM10-facilitated allergic sensitization. We demonstrate the importance of the lung NLRP3 inflammasome in mediating PM10 exposure-associated innate, but not adaptive, immune responses. Our study highlights a mechanism by which PM10 exposure can contribute to the exacerbation of airway disease, but not PM10-facilitated allergic sensitization.

Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin

“…A recent paper demonstrated that particulate matter, known to facilitate allergic sensitization, could also induce uric acid production by airway ECs, but in a TLR4‐independent manner . Although particulate matter was able to activate an innate response in ECs via NLRP3/IL‐1β inflammasome pathway, this pathway was completely dispensable for the facilitation of allergic sensitization . In agreement with these findings, we found that the type 2 immunity‐promoting effect of uric acid was not dependent on NLRP3/IL‐1β signaling, nor was it affected by the lack of ASC or caspase‐1 .…”

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study

“…DE-associated augmentation of select allergenic phenomena was shown in a human nasal model,15 16 and similar findings were noted with other particulate exposures 17 18. Still, DE's enhancement of allergenic effects has never been demonstrated in vivo in the distal human lung, a site of pathological importance in allergic disease, and the underlying details of this potential synergy are poorly understood.…”

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

“…The expression of NOD1 has been shown to be downregulated during pollen season among patients with allergic rhinitis [20], and its normal activation can reduce airway hyperresponsiveness accompanied by a reduction of allergen-specific T-cell proliferation in allergen-induced lung inflammation [21]. NLRP3 mediates cellular responses to inhaled particular matter (e.g., PM10) and has recently been elegantly shown to have an important role in innate but not adaptive immune responses in airway epithelial cells [22]. A novel NLR termed NLRX-1 has been identified in nasal epithelium that is activated by double-stranded RNA and participates in rhinoviral-mediated disruption of polarized airway epithelial cell barrier function [23].…”