Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade

Abstract

Ozone is a common environmental air pollutant leading to respiratory illness. The mechanisms regulating ozone-induced airway inflammation remain poorly understood. We hypothesize that ozone-triggered inflammasome activation and interleukin (IL)-1 production regulate neutrophilic airway inflammation through IL-17A. Pulmonary neutrophilic inflammation was induced by extended (72 h) low-dose (0.7 ppm) exposure to ozone. IL-1 receptor 1 (Il1r1)−/−, Il17a−/− mice and the caspase-1 inhibitor acetyl-YVAD-chloromethylketone (Ac-YVAD-cmk) were used for in vivo studies. Cellular inflammation and protein levels in bronchial alveolar lavage fluid (BALF), cytokines, and IL-17A-producing γδT-cells, as well as mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) release, and inflammasome activation in lung macrophages were analyzed. Ozone-induced neutrophilic airway inflammation, accompanied an increased production of IL-1β, IL-18, IL-17A, Granulocyte-colony stimulating factor (G-CSF), Interferon-γ inducible protein 10 (IP-10) and BALF protein in the lung. Ozone-induced IL-17A production was predominantly in γδT-cells, and Il17a-knockout mice exhibited reduced airway inflammation. Lung macrophages from ozone-exposed mice exhibited higher levels of mitochondrial ROS, enhanced cytosolic mtDNA, increased caspase-1 activation, and higher production of IL-1β. Il1r1-knockout mice or treatment with Ac-YVAD-cmk decreased the IL-17A production and subsequent airway inflammation. Taken together, we demonstrate that ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade.

Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33

“…Recent studies have demonstrated the importance of the TNF-a, IL-1, and IL-17A axis in an ozone-induced lung inflammation model using gene-deficient mice. [22][23][24][25]58,59 This is the first report demonstrating acute lung epithelial disruption and cell death with IL-33 release on a single ozone exposure (1 ppm for 1 hour) reminiscent of acute protease or cigarette smoke-induced lung injury/inflammation. 46,60 We postulated that the IL-33/ST2 axis might have a protective effect because genetic absence of IL-33 or ST2 and ST2 antibody blockade in mice augmented lung injury and inflammation.…”

Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy?

“…Also, a high correlation between nitrogen dioxide (NO 2 ) and particulate in inducing IL-6 hyperexpression was found (Perret et al, 2017), being both responsible of an inflammatory status even in a pediatric population (Gruzieva et al, 2017). Among the other more common pollutants, ozone (O 3 ) and sulfur dioxide (SO 2 ) have also a prominent role in inducing systemic and respiratory system inflammation, particularly via IL-8 (Kurai et al, 2018), IL-17 (Che et al, 2016) and TNF-a (Cho et al, 2007), both in vitro and in vivo (Knorst et al, 1996). All these modifications are well known to contribute to atherogenesis, chronic respiratory diseases and cardiovascular events, the latter strictly correlated with IL-6 serum levels (Aromolaran et al, 2018).…”

Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

“…Consistent with our previous study [ 20 ], the present study showed that multiple ozone exposure induced an increase in serum 8-OHdG, but not in BAL MDA. A recent study showed that increased mtROS was observed in lung macrophages after 72 h of 0.7 ppm ozone exposure [ 25 ]. We here demonstrated that elevated mtROS levels in lung tissue of mouse by multiple ozone exposure.…”