Late Breaking Abstract - Pulmonary localization and enrichment of IL1RAP in fibrotic interstitial lung diseases

The interleukin receptor accessory protein (IL1RAP), essential for downstream signaling of IL-1, IL-33 and IL-36, is involved in inflammation and fibrosis. It was recently shown that IL1RAP levels are increased in skin from systemic sclerosis (SSc) patients and that inhibition of IL1RAP reduced skin and lung fibrosis in three SSc mouse models. We hypothesize that IL1RAP is also upregulated in human lung tissue from patients with interstitial lung diseases (ILDs). <bold>Methods:</bold> IL1RAP expression was examined with immunofluorescence in explanted distal lung tissue of healthy donors (ctrl, n=6), idiopathic pulmonary fibrosis (IPF, n=6) and SSc patients with lung fibrosis (SSc-ILD, n=5). Staining for IL1RAP+cells was done in combination with markers for epithelial (pan-CK), immune/macrophage (CD45+CD68), endothelial (CD31), and smooth muscle/mesenchymal (aSMA+CD248) cells. Image analysis was done using a custom Python script. Cell nuclei were segmented with Stardist. <bold>Results:</bold> IL1RAP was localized to bronchiolar/alveolar epithelium, endothelial, and with highest expression in smooth muscle cells and macrophages. Pathological features (fibroblast foci, honeycomb cysts) in IPF and SSc-ILD were enriched with IL1RAP+cells. Overall, IPF and SSc-ILD had higher percentage of IL1RAP+ cells for all populations, apart from smooth muscle cells, compared to healthy (e.g. epithelial cells: 16%±6 SSc-ILD, 16%±2 IPF, ctrl 9%±1; endothelial: 14%±5 SSc-ILD, 13%±2 IPF, ctrl 10%±1). <bold>Conclusion:</bold> IL1RAP expression in lungs correlated to several cell types important for fibrotic lung disease. Targeting IL1RAP may therefore counteract pathological signaling in ILDs.