Sodium-coupled neutral amino acid transporter SNAT2 – a novel regulator of alveolar epithelial cell apoptosis and the innate immune response in acute lung injury/ARDS

• Applicant: Professor Dr. Wolfgang Kübler
• Subject Area: Anaesthesiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441105380

Acute respiratory distress syndrome (ARDS), a severe complication of e.g. pneumonia, sepsis, or COVID-19, constitutes the primary cause of mortality in ICU patients, and presently lacks effective pharmacological interventions. ARDS is characterized by lung hyperinflammation and epithelial apoptosis with a subsequent loss of alveolar barrier function. In the present project proposal, we postulate that these pathological processes are critically regulated by the sodium-coupled neutral amino acid transporter SNAT2. In the previous funding period, we had identified SNAT2 as a novel transporter in the alveolar epithelium. Concentrating on its ion channel function, we demonstrated its essential role in alveolar fluid clearance and lung edema resolution. In the current project, we now redirect our focus on SNAT2’s role as an essential amino acid transporter and its impact on cell metabolism in both alveolar epithelial and innate immune cells in ARDS. In a series of preliminary experiments we show that SNAT2 is downregulated in alveolar epithelial cells exposed to inflammatory mediators characteristic of ARDS, and that this loss-of-function induces alveolar epithelial cell death, presumably via an excessive increase in autophagy and apoptosis. In parallel, we have identified SNAT2 expression in innate immune cells including neutrophils and macrophages, in which SNAT2 is required for adequate inflammatory responses such as respiratory burst and phagocytosis. Based on these proof-of-principle data, we aim to explore the cellular mechanisms by which SNAT2 regulates epithelial cell survival and innate immune cell function, and the relevance of this regulation in the context of ARDS. Specifically, we hypothesize that SNAT2-mediated uptake of the amino acid glutamine and subsequent intracellular glutamine metabolism sustain energy production and the synthesis of cellular building blocks under environmental stress. In this way, SNAT2 may promote epithelial cell proliferation and alveolar barrier recovery, while in parallel driving the inflammatory functions of innate immune cells. Using mouse models of acute lung injury with cell type-specific SNAT2 deletion and in vitro assays in primary isolated cells, we will investigate the effects of SNAT2 gain- or loss-of-function and glutamine deprivation or replenishment, respectively, on cell metabolism, proliferative, autophagic and apoptotic signaling pathways, and inflammatory responses. We propose that by sustaining the alveolar epithelial barrier and promoting (hyper)inflammation, SNAT2 may play a Janus-faced role in the pathophysiology of ARDS. As such, strategies targeted to modulate SNAT2 in a cell type-specific manner may present the most promising therapeutic approach. In this project, we strive to advance our understanding of the molecular mechanisms of ARDS, a major unmet medical need, with the goal to establish SNAT2 as a potential therapeutic target to improve outcome in critically ill patients.

• DFG Programme: Research Grants