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

Abstract Background Asthma is an inflammatory disease that involves airway hyper‐responsiveness and mucus hypersecretion. The LIM ‐only protein FHL 2 is a crucial modulator of multiple signal transduction pathways and functions as a scaffold in specific protein–protein interactions. Objective We sought to investigate the role of FHL 2 in airway inflammation. Methods Allergic airway inflammation was induced in WT and FHL 2‐knock out ( FHL 2‐ KO ) mice with ovalbumin ( OVA ). Lung tissue, bronchoalveolar lavage fluid ( BALF ) and draining lymph node cells were analysed for inflammation. FHL 2 loss and gain of function studies were performed in lung epithelial cells. Results FHL 2‐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 FHL 2‐ KO mice. In BALF , the levels of IL‐5, IL‐13, eotaxin‐1 and eotaxin‐2 were significantly lower in FHL 2‐ KO mice. In addition, draining lymph node cells from FHL 2‐ KO mice show reduced levels of IL‐5 and IL‐13. Consistent with this, OVA ‐specific serum IgG and IgE levels were reduced in FHL 2‐ KO mice. We also found that phosphorylation of ERK 1/2 is markedly attenuated in FHL 2‐ KO lung. Knock‐down of FHL 2 in human lung epithelial cells resulted in a striking decrease in ERK 1/2 phosphorylation and m RNA levels of inflammatory cytokines and MUC 5AC, whereas FHL 2 overexpression exhibited opposite effects. Finally, the SNP rs4851765 shows an association with the severity of bronchial hyper‐responsiveness. Conclusion These results highlight functional involvement of FHL 2 in airway inflammation and identify FHL 2 as a novel gene associated with asthma severity in human.