Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone
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 Cc… Show more
“…Regardless of genotype, chemerin, one of two endogenous ligands for CMKLR1, was significantly greater in BAL fluid obtained from O 3 ‐ as compared to air‐exposed mice (Figure 1b ), which is consistent with our previous data (Malik et al., 2017 ; Razvi et al., 2015 ). However, independent of exposure, BAL chemerin was at least three‐fold greater in CMKLR1‐deficient as compared to wild‐type mice, and this observation is not without precedent.…”
Section: Discussionsupporting
confidence: 92%
“…Differences exist between 7-and 39-week-old mice with regard to O 3 -lung inflammation and antioxidant gene expression (Shore et al, 2011), and thus, age is another plausible explanation as to the reason differences in lung Cmklr1 mRNA expression exist between our study and that of Kilburg-Basnyat et al (2018). Regardless of genotype, chemerin, one of two endogenous ligands for was significantly greater in BAL fluid obtained from O 3 -as compared to airexposed mice (Figure 1b), which is consistent with our previous data (Malik et al, 2017;Razvi et al, 2015). However, independent of exposure, BAL chemerin was at least three-fold greater in CMKLR1-deficient as compared to wild-type mice, and this observation is not without precedent.…”
Section: Discussionsupporting
confidence: 91%
“…After airway responsiveness measurements were complete and while the animals remained under anesthesia, each mouse was euthanized by exsanguination after transecting the heart, which was accessed by performing a thoracotomy. Finally, more details concerning these methods have been previously described (Barreno et al., 2013 ; Malik et al., 2017 ).…”
We executed this study to determine if chemerin‐like receptor 1 (CMKLR1), a Gi/o protein‐coupled receptor expressed by leukocytes and non‐leukocytes, contributes to the development of phenotypic features of non‐atopic asthma, including airway hyperresponsiveness (AHR) to acetyl‐β‐methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non‐atopic asthma in wild‐type mice and mice incapable of expressing CMKLR1 (CMKLR1‐deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non‐atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi‐functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1‐deficient as compared to wild‐type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype‐related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype‐related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.
“…Regardless of genotype, chemerin, one of two endogenous ligands for CMKLR1, was significantly greater in BAL fluid obtained from O 3 ‐ as compared to air‐exposed mice (Figure 1b ), which is consistent with our previous data (Malik et al., 2017 ; Razvi et al., 2015 ). However, independent of exposure, BAL chemerin was at least three‐fold greater in CMKLR1‐deficient as compared to wild‐type mice, and this observation is not without precedent.…”
Section: Discussionsupporting
confidence: 92%
“…Differences exist between 7-and 39-week-old mice with regard to O 3 -lung inflammation and antioxidant gene expression (Shore et al, 2011), and thus, age is another plausible explanation as to the reason differences in lung Cmklr1 mRNA expression exist between our study and that of Kilburg-Basnyat et al (2018). Regardless of genotype, chemerin, one of two endogenous ligands for was significantly greater in BAL fluid obtained from O 3 -as compared to airexposed mice (Figure 1b), which is consistent with our previous data (Malik et al, 2017;Razvi et al, 2015). However, independent of exposure, BAL chemerin was at least three-fold greater in CMKLR1-deficient as compared to wild-type mice, and this observation is not without precedent.…”
Section: Discussionsupporting
confidence: 91%
“…After airway responsiveness measurements were complete and while the animals remained under anesthesia, each mouse was euthanized by exsanguination after transecting the heart, which was accessed by performing a thoracotomy. Finally, more details concerning these methods have been previously described (Barreno et al., 2013 ; Malik et al., 2017 ).…”
We executed this study to determine if chemerin‐like receptor 1 (CMKLR1), a Gi/o protein‐coupled receptor expressed by leukocytes and non‐leukocytes, contributes to the development of phenotypic features of non‐atopic asthma, including airway hyperresponsiveness (AHR) to acetyl‐β‐methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non‐atopic asthma in wild‐type mice and mice incapable of expressing CMKLR1 (CMKLR1‐deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non‐atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi‐functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1‐deficient as compared to wild‐type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype‐related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype‐related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.
“…On days 7, 14, 21, 28 and 33 of the bleomycin treatment regimen, respiratory system mechanics and P–V relationships were measured using the flexiVent (SCIREQ Inc., Montreal, QC, Canada) as previously described (Dahm et al., ; Karmouty‐Quintana et al., , ; Malik et al., ). In brief, the mice were anaesthetized with pentobarbital sodium (50 mg kg −1 , i.p ., Oak Pharmaceuticals, Inc.; Lake Forest, IL, USA) and xylazine hydrochloride (7 mg kg −1 , i.p ., Vedco Inc.; Saint Joseph, MO, USA).…”
New Findings
What is the central question of this study?When do alterations in pulmonary mechanics occur following chronic low‐dose administration of bleomycin?
What is the main finding and its importance?Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single‐frequency forced oscillation manoeuvres and pressure–volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic.
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure–volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure–volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.
“…CCRL2 genetically deficient mouse models have facilitated research on the function of CCRL2 in homeostasis and disease [16,17,[47][48][49], however, studies demonstrating the functional translation to humans are still lacking. While little is known about the function of CCRL2 in monocytes, previous work showed that human CD14 + monocytes express CCRL2 [35,50].…”
C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation.
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