Bronchial Epithelial Cells Promote the Differentiation of Th2 Lymphocytes in Airway Microenvironment through Jagged/Notch-1 Signaling after RSV Infection

Abstract

Background: The aim of this study was to investigate the role of Notch-1 signaling through Notch-1 ligands on bronchial epithelial cells (BECs) in regulating the development of T helper 2 (Th2) lymphocytes after RSV infection. Methods: Firstly, we analyzed the expression of cytokines and Notch-1 ligands in BECs by using real-time PCR. Then, RSV-infected BECs were co-cultured with CD4⁺ T cells in a transwell chamber for 48 h, and differentiation of T cells in the lower chamber was determined using flow cytometry and real-time PCR. JAG1 siRNA was then used to determine the effects of Jagged/Notch-1 signaling on the differentiation of Th2. An RSV-infected mouse model was also used to analyze the secretion of Th differentiation-associated cytokines in serum and lung tissues using ELISA, the histopathological changes using HE staining, and the expression of JAG1 and JAG2 in BECs. Results: The results showed that RSV promoted the expression of Th2-type cytokines and Jagged-1 and inhibited the expression of Jagged-2 in normal BECs. RSV-infected BECs induced Th2 differentiation. In addition, JAG1 downregulation inhibited the differentiation of Th2 and promoted differentiation of Th1. In the RSV-infected mouse model, the RSV titer, inflammation decreased with time. IL-4 and IL-17 increased on day 28 and 60, while IFNγ increased on day 7 and 28. Moreover, the expression of Jagged-1 increased and that of Jagged-2 decreased in BECs, which was consistent with IL-4 production in lung tissues. Conclusion: Our data showed that BECs had the potential to promote the differentiation of Th2 lymphocytes through Jagged-1/Notch-1 signaling.

Suppressive effects of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma

“…1, 5, and 6, they enhance the production of MCP-1, IL-6, and IL-8, resulting in the subsequent suppression of neutrophil apoptosis. Bronchial cells express various cytokines that regulate the Th1, Th2, and Th17 immune responses [21,22]. A recent study reported that S100A9 triggers the development of neutrophilic inflammation by elevation of IL-1β, IL-17 and IFN-γ, and induces allergen-induced Th2 type inflammation by production of thymic stromal lymphopoietin (TSLP) and IL-2 production [23,24].…”

COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm?

“…Conversely, the reduction of Jagged1 expression with siRNA abrogates this effect and promotes an increase in Th1 differentiation. On this basis, it has been suggested that Jagged1-mediated Th2 differentiation may cause RSV-induced airway hyperresponsiveness [37]. On the basis of these studies, it could be hypothesised that it may be preferable targeting specific components of the Notch signalling, such as Dll4 or Jagged1, rather than inhibiting Notch with a GSI.…”

Innate Immune Components That Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections

“…For hRSV, epithelial cells have been seen to contribute to the promotion of local inflammation and angiogenesis, the recruitment of various inflammatory cell types, and the development of a harmful T H 2 adaptive immune response. Many of these studies are based on in vitro models, and we only discuss the secretion of cytokines that have been observed in at least one type of human primary cell culture [ 118 , 230 , 247 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 ].…”

“…These cytokines greatly influence antigen-presenting cells and ILC2s, driving IL-4, IL-5, and IL-13 secretion that will ultimately lead to antibody-mediated adaptive immune responses, rather than a cytotoxic response [ 288 ]. Moreover, epithelial cells have been found to interact with CD4 + T cells via the Jagged/Notch-1 contact-dependent axis, directly influencing T H 2 differentiation in vitro [ 289 ].…”