RATIONALE: Information is missing on the tissue cell expression patterns of interleukin 33 (IL-33) and splice variants of the IL-33 receptor ST2 in normal and chronic obstructive pulmonary disease (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 endothelial subsets. In COPD, patchy alveolar regions displayed markedly elevated capillary sST2 and numbers of ST2L+ and IL-33+ gCaps.
CONCLUSIONS: By unraveling 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 treatment strategies targeting this pathway in lung diseases.
}}, author = {{Andersson, Cecilia K and Siddhuraj, Premkumar and Jönsson, Jimmie and Ahlgren, Johan and Lindö, Caroline and Nys, Josquin A and Scott, Ian C and Lindstedt, Sandra and Kolbeck, Roland and Humbles, Alison A and Lutter, René and Sabogal Piñeros, Yanaika S and Jonkers, René E and Tufvesson, Ellen and Sandén, Caroline and Cohen, E Suzanne and Erjefält, Jonas S}}, issn = {{1535-4970}}, keywords = {{Humans; Pulmonary Disease, Chronic Obstructive/metabolism; Interleukin-33/metabolism; Interleukin-1 Receptor-Like 1 Protein; Mast Cells/metabolism; Male; Female; Aged; Middle Aged; Endothelial Cells/metabolism; Lung/metabolism; Receptors, Cell Surface/metabolism; Interleukins; RNA, Messenger/metabolism; Case-Control Studies}}, language = {{eng}}, month = {{07}}, number = {{7}}, pages = {{1495--1509}}, publisher = {{American Thoracic Society}}, series = {{American Journal of Respiratory and Critical Care Medicine}}, title = {{Mast cells and endothelial cells mediate interleukin-33 and ST2 responses in distal chronic obstructive pulmonary disease lungs}}, url = {{http://dx.doi.org/10.1093/ajrccm/aamag079}}, doi = {{10.1093/ajrccm/aamag079}}, volume = {{212}}, year = {{2026}}, }