Control of innate immune reactions by bronchial epithelial cells
Final Report Abstract
This project aimed to study the regulatory role of the local lung microenvironment on innate immune responses. Specifically, built on previous work, responses by professional innate immune cells in the lung should be studied for their modification by the actions of airway epithelial cells. In a first subproject we tried to analyze the role of epithelial-cell derived prostaglandin E2 and reactivation of glucocorticoids as locally produced factors that shape innate immune responses. However, both factors could not be substantiated to play a major role using cells from either mPGE1 or 11bHSD1 knockout mice. It seemed that other enzymes in these situations could substitute for the inhibitory activities. During the studies we established precision cut lung slices (PCLS) as an organoid system allowing to study the interplay of the various cell types in the lung. Performing infections experiments with P. aeruginosa that were originally intended to study whether infection results in a release of inhibition of innate cells from modulatory effects by the microenvironment, we made the interesting observation that only viable but not heat-killed bacteria induced a substantial transcriptomic change in the PCLS model. The results were interpreted as “viability” sensing, a concept that was suggested by others and which states, that viable microorganisms signify a higher level of threat to the immune systems and result in more vigorous immune responses. We therefore studied the mechanisms of viability sensing of P. aeruginosa in the lung microenvironment in more detail: We could identify pscF from the type three secretion system and the flagellum as vita-PAMPs that serve to recognize viability and induce a full-blown innate immune response in PCLS. Internalization of bacteria was critical for this process. In a further sub-project, we could show that ER stress, that occurs in infected airway epithelial cells, contributes to amplification of inflammatory responses by delivering additional MAPK activation. Thus, within bronchial epithelial cells, ER stress acts as a danger signal that serves as costimulator for full activation via Toll-like receptors. In a last part of the project, we could show that nuclear suppressor of cytokine signaling-1 (SOCS1) protein serves a role for barrier integrity in airway epithelial cells and contributes to regulation of a subset of NF-KB dependent genes. Nuclear SOCS1 regulates local immunity in the lung and exerts regulatory functions.
Publications
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(2016): Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells. J Innate Immun; 8(5):464-78
Mijošek V, Lasitschka F, Warth A, Zabeck H, Dalpke AH, Michael Weitnauer
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(2016): Nuclear localization of Suppressor of Cytokine Signaling (SOCS)-1 regulates local immunity in the lung. Front. Immunol. 7: 514
Zimmer J, Weitnauer M, Boutin S, Küblbeck G, Thiele S, Walker P, Lasitschka F, Lunding L, Orinska Z, Vock V, Arnold B, Wegmann M and Dalpke A
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(2017): Crosstalk between glucocorticoids and IL-4 modulates Ym1 expression in alternatively activated myeloid cells. Immunobiology 222(5): 759-767
Ng Kuet Leong N, Brombacher F, Dalpke AH and Weitnauer M
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(2020): Early cytokine induction upon Pseudomonas aeruginosa infection in murine precision cut lung slices depends on sensing of bacterial viability. Front Immunol, 11: 598636
Kolbe U, Yi B, Poth T, Saunders A, Boutin S, Dalpke A
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(2020): Pseudomonas aeruginosa Modulates the Antiviral Response of Bronchial Epithelial Cells. Front. Immunol. 11:96
Sörensen M, Kantorek J, Byrnes L, Boutin S, Mall MA, Lasitschka F, Zabeck H, Nguyen D and Dalpke AH
