Amendment history : Corrigendum ( March 2018 ) ALX receptor ligands define a biochemical endotype for severe asthma

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.

[1]  Wei Wu,et al.  Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease , 2017, American journal of respiratory and critical care medicine.

[2]  E. Bleecker,et al.  Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma , 2017, American journal of respiratory and critical care medicine.

[3]  E. Bleecker,et al.  Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. , 2016, The Lancet. Respiratory medicine.

[4]  S. Wenzel,et al.  Current concepts of severe asthma. , 2016, The Journal of clinical investigation.

[5]  Udo Oppermann,et al.  Inflammation activation and resolution in human tendon disease , 2015, Science Translational Medicine.

[6]  C. Serhan,et al.  Identification of resolvin D2 receptor mediating resolution of infections and organ protection , 2015, The Journal of experimental medicine.

[7]  E. R. Sutherland,et al.  Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. , 2014, American journal of respiratory and critical care medicine.

[8]  Charles N. Serhan,et al.  Pro-resolving lipid mediators are leads for resolution physiology , 2014, Nature.

[9]  Charles N Serhan,et al.  Resolution of acute inflammation in the lung. , 2014, Annual review of physiology.

[10]  J. Fahy.  Type 2 inflammation in asthma — present in most, absent in many , 2014, Nature Reviews Immunology.

[11]  E. Bleecker,et al.  International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma , 2013, European Respiratory Journal.

[12]  M. Perretti,et al.  Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses , 2013, Proceedings of the National Academy of Sciences.

[13]  E. Israel,et al.  Exhaled breath condensate eicosanoid levels associate with asthma and its severity. , 2013, The Journal of allergy and clinical immunology.

[14]  R. Budd,et al.  Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4+ T cells , 2013, Cell Death and Disease.

[15]  E. Israel,et al.  Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma , 2013, Science Translational Medicine.

[16]  Sheng-hua Wu,et al.  Efficacy and safety of 15(R/S)‐methyl‐lipoxin A4 in topical treatment of infantile eczema , 2013, The British journal of dermatology.

[17]  Ji Ming Wang,et al.  Annexin A1 Interaction with the FPR2/ALX Receptor , 2012, The Journal of Biological Chemistry.

[18]  S. Wenzel.  Asthma phenotypes: the evolution from clinical to molecular approaches , 2012, Nature Medicine.

[19]  J. McQualter,et al.  Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease , 2012, Proceedings of the National Academy of Sciences.

[20]  M. Perretti,et al.  FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin‐derived peptide‐stimulated phagocytosis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  D. Gilroy,et al.  Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways , 2010, Proceedings of the National Academy of Sciences.

[22]  D. Curran‐Everett,et al.  Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. , 2010, American journal of respiratory and critical care medicine.

[23]  W. Busse,et al.  Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. , 2008, American journal of respiratory and critical care medicine.

[24]  B. Levy,et al.  Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation , 2008, Nature Immunology.

[25]  B. Levy,et al.  Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  C. Serhan,et al.  Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation1 , 2007, The Journal of Immunology.

[27]  Takao Shimizu,et al.  The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo , 2006, Pharmacological Reviews.

[28]  B. Levy,et al.  Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury. , 2006, The American journal of pathology.

[29]  K. Hagihara,et al.  Essential role of STAT3 in cytokine‐driven NF‐κB‐mediated serum amyloid A gene expression , 2005, Genes to cells : devoted to molecular & cellular mechanisms.

[30]  L. Palmer,et al.  Diminished lipoxin biosynthesis in severe asthma. , 2005, American journal of respiratory and critical care medicine.

[31]  J. Bousquet,et al.  Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound. , 2005, The Journal of allergy and clinical immunology.

[32]  S. Büyüköztürk,et al.  Acute phase reactants in allergic airway disease. , 2004, The Tohoku journal of experimental medicine.

[33]  W. Busse,et al.  Future research directions in asthma: an NHLBI Working Group report. , 2004, American journal of respiratory and critical care medicine.

[34]  C. Serhan,et al.  Aspirin-Triggered Lipoxin A4 and B4 Analogs Block Extracellular Signal-Regulated Kinase-Dependent TNF-α Secretion from Human T Cells 1 , 2003, The Journal of Immunology.

[35]  R. Ye,et al.  Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. , 2003, Blood.

[36]  S. Marullo,et al.  Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor , 2002, Nature Medicine.

[37]  Eugene Y. Kim,et al.  Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4 , 2002, Nature Medicine.

[38]  A. Sher,et al.  Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity , 2002, Nature Immunology.

[39]  Ji Ming Wang,et al.  Differential Regulation of Formyl Peptide Receptor-Like 1 Expression During the Differentiation of Monocytes to Dendritic Cells and Macrophages1 , 2001, The Journal of Immunology.

[40]  C. Serhan,et al.  Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. , 2001, The American journal of pathology.

[41]  C. Serhan,et al.  Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation , 2000, The Journal of experimental medicine.

[42]  M. Freeman,et al.  Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. , 1999, The Journal of clinical investigation.

[43]  W. Gong,et al.  A Seven-transmembrane, G Protein–coupled Receptor, FPRL1, Mediates the Chemotactic Activity of Serum Amyloid A for Human Phagocytic Cells , 1999, The Journal of experimental medicine.

[44]  C. Serhan,et al.  Activation of human monocytes and the acute monocytic leukemia cell line (THP-1) by lipoxins involves unique signaling pathways for lipoxin A4 versus lipoxin B4: evidence for differential Ca2+ mobilization. , 1996, Journal of immunology.

[45]  C. Serhan,et al.  Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor , 1994, The Journal of experimental medicine.

[46]  B. Spur,et al.  The effects of lipoxin A4 on airway responses in asthmatic subjects. , 1992, The American review of respiratory disease.

[47]  V. Gant,et al.  Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage fluids obtained from patients with selected pulmonary diseases. , 1990, The American review of respiratory disease.