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, the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators
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
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Clinical Research and Public Health Inflammation Pulmonology

ALX receptor ligands define a biochemical endotype for severe asthma

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

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Figure 4

SAA and macrophage ALX expression are associated with increased symptoms in severe asthma.

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SAA and macrophage ALX expression are associated with increased symptoms...
Asthma subjects were categorized into subgroups based on low or high BALF levels of SAA (A–D), LXA4 (E–H), and macrophage ALX expression (I–L). The median value for each variable was used to define the cutoff between the low and high subgroups (SAA cutoff = 1.22 pg/μg protein, LXA4 cutoff = 0.25 pg/μg protein, ALX index cutoff = 4.6 pg/μg protein). Cutoff values are delineated by the gray vertical line. A histogram shows the distribution of subjects based on BALF (A) SAA level, (E) LXA4 level, and (I) BAL macrophage ALX index. (B, F, and J) Validated measures of asthma symptoms (ACQ and ACT scores) were compared between low (open diamonds) and high (closed diamonds) subgroups for SAA, LXA4, and ALX index. (C, G, and K) The distributions of SAA, LXA4, and ALX index among NSA (blue) and SA (red) subjects are shown in violin plots. (D, H, and L) ACQ and ACT scores were compared in SA subjects for low (open triangles) and high (closed triangles) subgroups for SAA, LXA4, and ALX index. Scatter plots show individual subject data with mean ± SEM. n = 51 NSA and n = 69 SA subjects.*P < 0.05, **P < 0.01 by Mann-Whitney test or 2-tailed Student’s t test. BALF, bronchoalveolar lavage fluid; SAA, serum amyloid A; ACQ, asthma control questionnaire; ACT, asthma control test; NSA, nonsevere asthma; SA, severe asthma; LXA4, lipoxin A4; ALX, airway lipoxin A4 receptor.