Critical Role for the NLRP3 Inflammasome during Acute Lung Injury

Abstract

The inflammasome is a key factor in innate immunity and senses soluble pathogen and danger associated molecular patterns as well as biological crystals (urate, cholesterol, etc.), resulting in expression of IL-1β and IL-18. Using a standard model of acute lung injury (ALI) in mice featuring airway instillation of LPS, ALI was dependent on availability of NLRP3 as well as caspase-1, which are known features of the NLRP3 inflammasome. The appearance of IL-1β, a product of NLRP3 inflammasome activation, was detected in bronchoalveolar lavage fluids (BALF) in a macrophage- and neutrophil-dependent manner. Neutrophil-derived extracellular histones appeared in the BALF during ALI and directly activated the NLRP3 inflammasome. Antibody-mediated neutralization of histones significantly reduced IL-1β levels in BALF during ALI. Inflammasome activation by extracellular histones in LPS-primed macrophages required NLRP3 and caspase-1 as well as extrusion of K+, increased [Ca+2]i, and generation of reactive oxygen species. NLRP3 and caspase-1 were also required for full extracellular histone presence during ALI, suggesting a positive feedback mechanism. Extracellular histone and IL-1β levels in BALF were also elevated in C5a-induced and IgG immune complex ALI models suggesting a common inflammatory mechanism. These data indicate an interaction between extracellular histones and the NLRP3 inflammasome, resulting in ALI. Such findings suggest novel targets for treatment of ALI, for which there is currently no known efficacious drug.

Anti-inflammatory effect of Impatiens textori Miq. extract via inhibition of NLRP3 inflammasome activation in in vitro and in vivo experimental models

“…instillation of LPS stimulates airway epithelial cells to release proinflammatory cytokines, such as IL-1β and TNF-α, which causes subsequent neutrophilic infiltration and ultimately results in lung tissue injury in an LPS-induced ALI mouse model. In a recent study, knockout mice in an NLRP3 inflammasome component showed lower level of immune cell recruitment such as neutrophils in an LPS-induced ALI mouse model than wild-type mice (Grailer et al, 2014). Therefore, we extended our work to the ALI in vivo mouse model to support our in vitro data.…”

“…LPS-induced ALI model was used as described previously (Grailer et al, 2014;Shim et al, 2013). Briefly, LPS (5 mg/kg) was instilled intranasally (i.n.)…”

Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis

“…In the context of these previous findings, we hypothesized that the IL-23-induced decrease in Bcl-2 might result in enhanced ROS generation, which in turn would further drive apoptosis susceptibility in macrophages exposed to athero-relevant pro-apoptotic factors. To address this hypothesis, we incubated macrophages with 7KC in the absence or presence of IL-23 and then probed the cells with CellROX Deep Red ™ , which fluoresces in the cytoplasm when exposed to ROS 43 . Similar to the apoptosis findings, IL-23 alone did not induce ROS in macrophages, but it enhanced ROS in the presence of 7KC (Figure 8A and Online Figure XXIIIA).…”

Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

“…Studies have shown IL-9 (38), TNF (39), and chemokine (40) production by neutrophils in response to RSV. Neutrophils are a source of IL-1␤ in lung injury models (41), but this is the first study that has demonstrated IL-1␤ production by neutrophils in response to respiratory viral infection. Airway neutrophilia is observed in patients with bronchiolitis (42), and an increase in neutrophils is detected in blood prior to the influx of CD8 T cells (43).…”