No abstract

Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world and is characterized by inflammation, emphysema and respiratory dysfunction. The development of radical treatment and the achievement of long-term disease management are urgent issues for COPD. Because COPD is highly complicated with lung cancer and this complication leads to poor prognosis, it is very important to elucidate its pathological mechanism and develop a novel therapeutic strategy. Previous research showed the relationship between lung cancer and COPD-derived inflammation, but not emphysema. Therefore, I selected elastase model and induced lung cancer using tobaccospecific carcinogenesis (NNK) for lung cancer initiation stage model (COPD-NNK) and lewis lung carcinoma (LLC) for lung cancer exacerbation stage (COPD-LLC). In COPD-NNK model, incidence of lung tumors was increased but COPD phenotypes were not exacerbated. Moreover, I found that α7nAChR-p-Akt pathway was activated in these tumors. Additionally, the survival rate was decreased and intratumor T cells and immune checkpoint protein PD-L1positive macrophages were increased in COPD-LLC model. In contrast, the survival rate was increased in anti-PD-L1 antibody-treated COPD-LLC model. These results suggested that PD-L1-positive macrophages inhibited T cell activity and decreased the survival rate. In this study, I revealed changes in tumor microenvironment and exacerbation mechanism in COPD-lung cancer complication.