Mast Cells and Endothelial Cells Mediate Interleukin-33 and ST2 Responses in Distal COPD Lungs

Abstract Rationale Information is missing on the tissue cell expression patterns of interleukin IL-33 (IL-33) and splice variants of the IL-33 receptor ST2 in normal and COPD lungs. Objectives To characterize the expression patterns of IL-33, the soluble ST2 (sST2) and membrane-bound ST2 (ST2L) splice variants in the poorly studied small airway and distal lung compartments in COPD and controls. Methods Surgically excised lung tissue was collected from 38 COPD patients and 21 non-COPD controls. Lung compartment expression of IL-33 and ST2 and key expressing cell types were assessed histologically by combined in situ hybridization and multiplex immunohistochemistry. Expression dynamics of IL-33, ST2L and sST2 were explored by spatially resolved single-cell analysis. Measurements and Main Results COPD lungs displayed increased IL-33 mRNA and IL-33 mRNA/protein ratios, suggesting increased IL-33 turnover. Total ST2/IL1RL1 mRNA levels were upregulated in COPD lungs. Mast cells constituted the major ST2-expressing immune cell population in controls and displayed a microenvironmental-specific upregulation of both ST2L and sST2 in COPD. In control alveolar regions, ST2Lhigh sST2high mast cells were present alongside IL-33-expressing general capillary (gCAp) and sST2moderate ST2Llow aerocyte (aCap) endothelial subsets. In COPD patchy alveolar regions displayed markedly elevated capillary sST2 and numbers of ST2L + and IL-33 + gCaps. Conclusions By unravelling the expression patterns of IL-33 and the biologically opposing ST2L and sST2 splice variants in control and COPD lungs, the present study provides novel insights into IL-33-mediated immunity in the distal lung, information that has bearing on treatments strategies targeting this pathway in lung diseases.