ALX receptor ligands define a biochemical endotype for severe asthma
Isabell Ricklefs, Ioanna Barkas, Melody G. Duvall, Manuela Cernadas, Nicole L. Grossman, Elliot Israel, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Loren C. Denlinger, David T. Mauger, Sally E. Wenzel, Suzy A. Comhair, Andrea M. Coverstone, Merritt L. Fajt, Annette T. Hastie, Mats W. Johansson, Michael C. Peters, Brenda R. Phillips, Bruce D. Levy, and the National Heart Lung and Blood Institute’s Severe Asthma Research Program- Investigators
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First published March 22, 2018 - More info
JCI Insight. 2018;3(6):e120932. https://doi.org/10.1172/jci.insight.120932.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
BACKGROUND. In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS. ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS. Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS. Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation. TRIAL REGISTRATION. Severe Asthma Research Program-3 (SARP-3; ClinicalTrials.gov NCT01606826) FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.
Authors
Isabell Ricklefs, Ioanna Barkas, Melody G. Duvall, Manuela Cernadas, Nicole L. Grossman, Elliot Israel, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Loren C. Denlinger, David T. Mauger, Sally E. Wenzel, Suzy A. Comhair, Andrea M. Coverstone, Merritt L. Fajt, Annette T. Hastie, Mats W. Johansson, Michael C. Peters, Brenda R. Phillips, Bruce D. Levy, the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators
Original citation: JCI Insight. 2017;2(14):1–14. https://doi.org/10.1172/jci.insight.93534
Citation for this corrigendum: JCI Insight. 2018;3(6):e120932. https://doi.org/10.1172/jci.insight.120932
Following the publication of this article, the authors became aware that there was an error in calculating the FEV1 percentage predicted, FVC percentage predicted, and FEV1/FVC percentage predicted values for subjects of mixed European descent in the SARP cohort. Correcting this error resulted in lower FEV1 and FVC percentage predicted values and slightly higher FEV1/FVC percentage predicted values — and required corrections to the spirometry data presented in Table 1, Figure 2, Figure 5F, and Supplemental Figure 2, A and B. These corrections do not change the finding that lipoxin A4 levels positively correlate with lung function in asthma and that subjects with SAAhiLXA4lo levels have lower lung function than subjects with SAAloLXA4hi levels nor do they alter the conclusions of the study.
Table 1Clinical characteristics and bronchoalveolar lavage leukocytes for subjects undergoing bronchoscopyA
The corrected versions of Figure 2, Figure 5F, and Table 1 are below. The posted supplemental data have been updated.
The authors regret the errors.
