Hedgehog interacting protein–expressing lung fibroblasts suppress lymphocytic inflammation in mice

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.