Project Details
Projekt
Mechanical stretch of alveolar epithelia induces heterotypic activation of alveolar macrophages
Applicant
Professor Dr. Manfred Frick
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564756447
Alveoli are the central functional units of the lung. Maintaining alveolar homeostasis and lung function depends on a tight interplay of alveolar epithelial cells (AECs) with mesenchymal and immune cells. Several interactions have been identified that preserve the alveolar niche, promote acute inflammation and wound healing in response to injury. AECs form direct, heterotypic cell-cell connections with tissue-resident alveolar macrophages (AMs), the main immune cell population in the alveoli. Heterotypic cell-cell connections between AMs and AECs include surface protein interactions and gap junctions and modulate the response to infection via transmission of Ca2+ signals. Notably, AM mediated immune responses can also occur in the absence of infection. This phenomenon has been observed in cases of mechanical ventilation, a critical therapy in severe lung disease, which can lead to ventilator-induced lung injury (VILI). It´s been hypothesized that inflammation is triggered in response to overdistension of the alveolar epithelium. The detailed mechanisms linking alveolar hyperinflation, epithelial overexpansion and inflammation are elusive. Interestingly these are attenuated by AM depletion. Based on these findings, we hypothesize that (over)extension of the alveolar epithelium triggers activation of AMs. This activation depends on heterotypic cell-cell interactions and Ca2+ signaling. To test this hypothesis, we will employ well-established in vitro models of the human alveolus. We will co-culture human AECs and AMs and investigate the activation of AMs in response to mechanical stretch of the epithelium. Subsequent analyses will focus on the Ca2+ signals in individual cells (epithelial cells, AMs) in response to the stretch of the alveolar epithelium, with the objective of elucidating the underlying molecular mechanisms for the epithelial-stretch-induced Ca2+ signals in AMs. This will include the analysis of the expression and localization of cell surface protein interactions and/or gap junctions at the epithelial-AM interface, as well as the inhibition and functional knockdown/knockout of specific proteins using pharmacological tools, siRNAs/shRNAs, and gene-editing. Finally, we will perform epithelial-stretch-dependent AM activation assays whilst selectively inhibiting the identified signaling pathways to determine the dependence of AM activation on specific heterotypic interaction of AECs with AMs and epithelial-stretch-induced Ca2+ signals in AMs. In summary, our study will provide novel insights into the role of the intrinsic heterotypic cellular interplay of AECs and AMs in the human alveolus. The study will elucidate the role of epithelial overstretching in activating AMs and identify the underlying mechanisms. These findings will contribute to our understanding of the pathogenesis of severe pulmonary inflammation and the development of ALI/ARDS upon hyperinflation of the lungs, as observed in ventilator-induced lung injury (VILI).
DFG Programme
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