Abstract
Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and characterized by chronic inflammation in vulnerable individuals. However, it is unknown how genetic factors may shape chronic inflammation in COPD. To understand how hedgehog interacting protein, encoded by HHIP gene identified in the genome-wide association study in COPD, plays a role in inflammation, we utilized Hhip+/– mice that present persistent inflammation and emphysema upon aging similar to that observed in human COPD. By performing single-cell RNA sequencing of the whole lung from mice at different ages, we found that Hhip+/– mice developed a cytotoxic immune response with a specific increase in killer cell lectin-like receptor G1–positive CD8+ T cells with upregulated Ifnγ expression recapitulating human COPD. Hhip expression was restricted to a lung fibroblast subpopulation that had increased interaction with CD8+ T lymphocytes in Hhip+/– compared with Hhip+/+ during aging. Hhip-expressing lung fibroblasts had upregulated IL-18 pathway genes in Hhip+/– lung fibroblasts, which was sufficient to drive increased levels of IFN-γ in CD8+ T cells ex vivo. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic inflammatory lung disease characterized by progressive airflow limitation
As frequent COPD exacerbation is associated with persistent airway and systemic inflammation [15], we examined whether hedgehog interacting protein (HHIP) COPD risk variant is associated with COPD exacerbation frequency
In a human COPD study, we found that the HHIP genetic variant is associated with exacerbation frequency, a key phenotype associated with active inflammation [30]
Summary
Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic inflammatory lung disease characterized by progressive airflow limitation. The hedgehog interacting protein (HHIP) locus on chromosome 4q31 is one of the most replicated loci, strongly associated with COPD in multiple genome-wide association studies (GWAS) [1,2,3,4]. It has been associated with severity and distribution of emphysema [5, 6] as well as with lung function, measured as forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC), in both smokers and nonsmokers [1, 7, 8]. HHIP was shown to be expressed in mesenchyme during murine lung development [10], it remains unclear which cell types express HHIP after lung development and how haploinsufficiency of HHIP results in lymphocytic inflammation
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