Increased IL‐6 and Potential IL‐6 trans‐signalling in the airways after an allergen challenge

• Published in: Clinical and experimental allergy Vol. 51; no. 4; pp. 564 - 573
• Main Authors: Esnault, Stephane, Khosravi, Mehdi, Kelly, Elizabeth A., Liu, Lin Ying, Bochkov, Yury A., Tattersall, Matthew C., Jarjour, Nizar N.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2021
• Series: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
• Subjects: Allergens; Allergies; allergy; Alveoli; Ambrosia; Animals; Asthma; Asthma - genetics; Asthma - metabolism; Bronchial Provocation Tests; bronchoalveolar lavage; Bronchoalveolar Lavage Fluid - chemistry; Bronchus; CCL2; Chemokine CCL2 - metabolism; Chemokines; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Dander; Epithelial cells; Female; Fibroblasts; Flow cytometry; Glycoprotein gp130; Humans; IL‐6; IL‐6 receptor; Inflammation; Interleukin-6 - genetics; Interleukin-6 - metabolism; Leukocytes (eosinophilic); Life Sciences; Lymphocytes; Male; Membrane proteins; Monocyte chemoattractant protein 1; Monocytes; Proteins; Pyroglyphidae; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - metabolism; RNA-Seq; trans‐signalling; Young Adult; fibroblasts; trans-signalling; IL-6 receptor; CCL2; allergy; asthma; bronchoalveolar lavage; IL-6; Bronchoalveolar Lavage Fluid; Allergens; Humans; Bronchial Provocation Tests; Male; Interleukin-6; Young Adult; Dander; Female; Respiratory Hypersensitivity; Cytokine Receptor gp130; Asthma; Ambrosia; Animals; RNA-Seq; Pyroglyphidae; Receptors, Interleukin-6; Chemokine CCL2
• ISSN: 0954-7894; 1365-2222; 1365-2222
• DOI: 10.1111/cea.13832

Background In asthma, IL‐6 is a potential cause of enhanced inflammation, tissue damage and airway dysfunction. IL‐6 signalling is regulated by its receptor, which is composed of two proteins, IL‐6R and GP130. In addition to their membrane form, these two proteins may be found as extracellular soluble forms. The interaction of IL‐6 with soluble IL‐6R (sIL‐6R) can trigger IL‐6 trans‐signalling in cells lacking IL‐6R. Conversely, the soluble form of GP130 (sGP130) competes with its membrane form to inhibit IL‐6 trans‐signalling. Objectives We aimed to analyse IL‐6 trans‐signalling proteins in the airways of subjects after an allergen challenge. Methods We used a model of segmental bronchoprovocation with an allergen (SBP‐Ag) in human subjects with allergy. Before and 48 h after SBP‐Ag, bronchoalveolar lavages (BALs) allowed for the analysis of proteins in BAL fluids (BALFs) by ELISA, and membrane proteins on the surface of BAL cells by flow cytometry. In addition, we performed RNA sequencing (RNA‐seq) and used proteomic data to further inform on the expression of the IL‐6R subunits by eosinophils, bronchial epithelial cells and lung fibroblasts. Finally, we measured the effect of IL‐6 trans‐signalling on bronchial fibroblasts, in vitro. Results IL‐6, sIL‐6R, sGP130 and the molar ratio of sIL‐6R/sGP130 increased in the airways after SBP‐Ag, suggesting the potential for enhanced IL‐6 trans‐signalling activity. BAL lymphocytes, monocytes and eosinophils displayed IL‐6R on their surface and were all possible providers of sIL‐6R, whereas GP130 was highly expressed in bronchial epithelial cells and lung fibroblasts. Finally, bronchial fibroblasts activated by IL‐6 trans‐signalling produced enhanced amounts of the chemokine, MCP‐1 (CCL2). Conclusion and Clinical relevance After a bronchial allergen challenge, we found augmentation of the elements of IL‐6 trans‐signalling. Allergen‐induced IL‐6 trans‐signalling activity can activate fibroblasts to produce chemokines that can further enhance inflammation and lung dysfunction.