IL1RL1 asthma risk variants regulate airway type 2 inflammation
Erin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, Max A. Seibold
Erin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, Max A. Seibold
View: Text | PDF
Research Article Immunology Pulmonology

IL1RL1 asthma risk variants regulate airway type 2 inflammation

Abstract

Genome-wide association studies of asthma have identified genetic variants in the IL1RL1 gene, but the molecular mechanisms conferring risk are unknown. IL1RL1 encodes the ST2 receptor (ST2L) for IL-33 and an inhibitory decoy receptor (sST2). IL-33 promotes type 2 inflammation, which is present in some but not all asthmatics. We find that two single nucleotide polymorphisms (SNPs) in IL1RL1 — rs1420101 and rs11685480 — are strongly associated with plasma sST2 levels, though neither is an expression quantitative trait locus (eQTL) in whole blood. Rather, rs1420101 and rs11685480 mark eQTLs in airway epithelial cells and distal lung parenchyma, respectively. We find that the genetically determined plasma sST2 reservoir, derived from the lung, neutralizes IL-33 activity, and these eQTL SNPs additively increase the risk of airway type 2 inflammation among asthmatics. These risk variants define a population of asthmatics at risk of IL-33–driven type 2 inflammation.

Authors

Erin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, Max A. Seibold

×

Figure 4

Plasma sST2 levels are correlated with the EC50 dose of IL-33 for whole blood cell activation.

Options: View larger image (or click on image) Download as PowerPoint
Plasma sST2 levels are correlated with the EC50 dose of IL-33 for whole ...
(A) Paired peripheral blood mononuclear cells (PBMC) and whole blood cells from human donors (n = 4; each color represents a unique subject) were stimulated with IL-12 and a biologically active variant of IL-33 with mutated cysteine residues. (B) Compared with PBMC, IL-33 signaling is more variable and markedly reduced in whole blood, suggesting the presence of an IL-33 inhibitor (n = 4). Statistical analysis performed using 2-tailed paired t test. (C) The level of plasma sST2 is significantly and positively associated with the half maximal effective concentration (EC50) for IL-33 in whole blood cells (n = 20). Simple linear regression with P value listed.