LIGHT in combination with IL-13 or IL-17 drives inflammatory transcriptional signatures in human pulmonary fibroblasts relevant for human lung disease.

Abstract

Fibroblasts are structural cells primarily involved in tissue remodeling, but recent single-cell RNA sequencing (RNA-seq) transcriptomic data have highlighted their potential to display molecules linked to inflammation. The factors that drive such inflammatory transcriptional signatures found in patients are not clear. LIGHT (TNFSF14) is a cytokine that we previously suggested may be central to lung diseases exhibiting fibrosis and inflammation, including asthma and interstitial lung disease. With bulk RNA-seq, we then investigated the transcriptional activity of LIGHT in human pulmonary fibroblasts compared with interleukin (IL)-13 and IL-17, two other cytokines linked to lung disease. While all 3 cytokines individually induced unique and overlapping gene transcripts, when fibroblasts were stimulated with LIGHT and IL-13 they upregulated more inflammatory transcripts including CCL2, CCL26, CXCL2, CXCL3, CXCL5, CXCL6, IL32, CSF2, VCAM1, ICAM1, IL18R1, IL1RL1, TNFRSF12A, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV, and when stimulated with LIGHT and IL-17, inflammatory transcripts included CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL32, IL33, CSF2, TSLP, IL1A, IL6, IL18, VCAM1, ICAM1, IL18R1, IL1RL1, TNFSF4, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV. Furthermore, multiple cell cycle-related transcripts were induced with these combinations. Providing potential disease significance, portions of the fibroblast transcriptional signatures induced in vitro were found to be present in subsets of fibroblasts defined by single-cell RNA-seq isolated from patients with interstitial lung disease. This study therefore highlights the synergistic activities of LIGHT with other classical cytokines to regulate transcription in pulmonary fibroblasts and infers the involvement of LIGHT in shaping fibroblast phenotypes observed in chronic lung disease.