Abstract
Inhalation of ozone (O3), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O3. Furthermore, each of these aforementioned cells express chemokine (C‐C motif) receptor‐like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O3‐induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O3, we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O3. To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl‐β‐methylcholine chloride (respiratory system resistance) in wild‐type and mice genetically deficient in Ccrl2 (Ccrl2‐deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O3. In air‐exposed mice, BALF chemerin was greater in Ccrl2‐deficient as compared to wild‐type mice. O3 increased BALF chemerin in mice of both genotypes, yet following O3 exposure, BALF chemerin was greater in Ccrl2‐deficient as compared to wild‐type mice. O3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O3‐induced lung pathology.
Highlights
Chemotactic cytokines, more commonly known as chemokines, direct leukocyte migration following interaction with seven-transmembrane domain receptors that are part of the chemokine receptor family (Bachelerie et al 2014)
A recent study by Del Prete et al (2017) reported that Ccrl2 influenced the ability of chemokine (C-X-C motif) receptor 2 (CXCR2), the receptor for keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2 (Konrad and Reutershan 2012), to promote neutrophil migration. This observation is relevant to our current study since we previously reported that CXCR2-deficient mice had fewer bronchoalveolar lavage fluid (BALF) neutrophils (Johnston et al 2005a)
We used Reverse transcription (RT)-quantitative realtime polymerase chain reactions (qPCR) to determine if the relative abundance of Ccrl2 messenger RNA (mRNA) was altered in the left lung lobe of wildtype mice 4 and 24 hours following cessation of exposure to O3
Summary
Chemotactic cytokines, more commonly known as chemokines, direct leukocyte migration following interaction with seven-transmembrane domain receptors that are part of the chemokine receptor family (Bachelerie et al 2014). Zabel et al (2008) identified chemerin, a nonchemokine chemoattractant for macrophages, natural killer cells, and plasmacytoid dendritic cells, as an endogenous ligand for Ccrl (Wittamer et al 2003; Zabel et al 2005; Parolini et al 2007; Bondue et al 2011), and in support of the classification of Ccrl as an atypical chemokine receptor, chemerin does not activate G protein signaling when binding Ccrl (De Henau et al 2016). From the observation that Ccrl increases local concentrations of bioactive chemerin (Zabel et al 2008), Zabel et al (2008) hypothesize that Ccrl may influence leukocyte migration by facilitating the conversion of inactive chemerin to bioactive chemerin that subsequently binds to and directs the migration of cells expressing Cmklr
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