T4 IL-1R1 expression on mesenchymal cells drives inflammation and fibrosis in response to epithelial damage in the lung

Abstract

Epithelial injury has been recognised as a key event in the pathogenesis of lung fibrosis.1 Damaged epithelial cells are a major source of danger signals referred to as alarmins or damage associated molecular patterns (DAMPs). Previously published work from our group has shown that IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts via an IL-1R1 dependant pathway.2 3 Critically mice that are globally deficient in IL-1α or IL-1R1 are protected from pulmonary fibrosis. In this study we specifically investigate the importance of IL-1R1 on fibroblasts using both ex-vivo and in-vivo models. IL-1R1 floxed mice were crossed with LysM Cre mice and PDGFRββ Cre mice to generate mice deficient in IL-1R1 expression in myeloid (IL-1R1ΔMono) and mesenchymal (IL-1R1ΔFib) cells. Initially, Precision Cut Lung Slices (PCLS) were prepared from IL-1R1ΔMono, IL-1R1ΔFib as well as IL-1R1 floxed mice, LysM Cre and PDGFRββ Cre control mice. Exogenous challenge with IL-1β induced a dose-dependent inflammatory response in PCLS from control mice as characterised by elevated secretion of IL-6, KC and CCL2. Critically, inflammation in PCLS from IL-1R1ΔFib mice was attenuates ˜70% whereas no effect was observed in PCLS from IL-1R1ΔMono mice. To determine the importance of IL-1R1 on fibroblasts in vivo we challenged IL-1R1ΔMono and IL-1R1ΔFib mice intratracheally with bleomycin. Critically IL-1R1ΔFib mice were protected from bleomycin induced pulmonary inflammation and fibrosis whereas IL-1R1ΔMono mice developed pulmonary fibrosis normally. In summary, the fibroblasts is the primary cell responding to epithelial damage in intact lung tissue and selective depletion of IL-1R1 on fibroblasts in vivo attenuates pulmonary inflammation and fibrosis. These data suggest that the fibroblasts directly drives pulmonary inflammation and fibrosis in response to epithelial damage. References Chambers CR, Mercer FP. Mechanisms of alveolar epithelial injury, repair, and fibrosis. ATS Journal 2015;12:S16–S20. Suwara MI, et al. IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immunology2014;7:684–93. Borthwick AL. Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction. American Journal of Transplantation2015;16:1751–65.