Deficiency of FHL2 attenuates airway inflammation in mice and genetic variation associates with human bronchial hyper‐responsiveness

• DOI: 10.1111/all.12709
• Publication Date: 2015-07-28T13:11:03Z
• Authors: K. Kurakula; M. Vos; A. Logiantara; J. J. T. H. Roelofs; M. A. Nieuwenhuis; G. H. Koppelman; D. S. Postma; C. A. Brandsma; D. D. Sin; Y. Bossé; D. C. Nickle; L. S. van Rijt; C. J. M. de Vries
• Keywords: 0301 basic medicine; FHL2; Genotype; LIM DOMAIN PROTEIN-2; Blotting, Western; LIM-Homeodomain Proteins; Muscle Proteins; airway inflammation; RESPIRATORY-TRACT; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Mice; 03 medical and health sciences; Respiratory Hypersensitivity; Animals; Humans; Genetic Predisposition to Disease; MUCIN GENES; Oligonucleotide Array Sequence Analysis; Mice, Knockout; RECEPTOR; bronchial hyper-responsiveness; SMOOTH-MUSCLE; Pneumonia; pERK1/2; epithelial cells; Asthma; 3. Good health; EOTAXIN; Mice, Inbred C57BL; Disease Models, Animal; CHEMOKINES; ONLY PROTEIN FHL2; CELLS; ASTHMA; Transcription Factors

AbstractBackgroundAsthma is an inflammatory disease that involves airway hyper‐responsiveness and mucus hypersecretion. The LIM‐only protein FHL2 is a crucial modulator of multiple signal transduction pathways and functions as a scaffold in specific protein–protein interactions.ObjectiveWe sought to investigate the role of FHL2 in airway inflammation.MethodsAllergic airway inflammation was induced in WT and FHL2‐knock out (FHL2‐KO) mice with ovalbumin (OVA). Lung tissue, bronchoalveolar lavage fluid (BALF) and draining lymph node cells were analysed for inflammation. FHL2 loss and gain of function studies were performed in lung epithelial cells.ResultsFHL2‐deficient mice challenged with OVA show significantly reduced airway inflammation as evidenced by reduced infiltration of inflammatory cells including eosinophils, dendritic cells, B cells and T cells. Furthermore, mucus production was decreased in FHL2‐KO mice. In BALF, the levels of IL‐5, IL‐13, eotaxin‐1 and eotaxin‐2 were significantly lower in FHL2‐KO mice. In addition, draining lymph node cells from FHL2‐KO mice show reduced levels of IL‐5 and IL‐13. Consistent with this, OVA‐specific serum IgG and IgE levels were reduced in FHL2‐KO mice. We also found that phosphorylation of ERK1/2 is markedly attenuated in FHL2‐KO lung. Knock‐down of FHL2 in human lung epithelial cells resulted in a striking decrease in ERK1/2 phosphorylation and mRNA levels of inflammatory cytokines and MUC5AC, whereas FHL2 overexpression exhibited opposite effects. Finally, the SNP rs4851765 shows an association with the severity of bronchial hyper‐responsiveness.ConclusionThese results highlight functional involvement of FHL2 in airway inflammation and identify FHL2 as a novel gene associated with asthma severity in human.