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Reimer Köster
Paper of the Month: January 2024

Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia

Nat Commun.
Pervizaj-Oruqaj L, Selvakumar B, Ferrero MR, Heiner M, Malainou C, Glaser RD, Wilhelm J, Bartkuhn M, Weiss A, Alexopoulos I, Witte B, Gattenlöhner S, Vadász I, Morty RE, Seeger W, Schermuly RT, Vazquez-Armendariz AI, Herold S.

Respiratory infections, such as those caused by influenza virus, highlight the critical need to comprehend the role of lung macrophages in both driving tissue injury and facilitating repair processes. Research has revealed that during influenza virus-induced pneumonia, tissue-resident alveolar macrophage (TR-AM) population is depleted and subsequently replaced by bone marrow-derived macrophages (BMDM). A key player identified in this process is Plet1, a membrane protein, which orchestrates a specific epithelial repair program in alveolar macrophages. This program entails a transition of macrophages from a pro-inflammatory, injury-promoting state to a tissue-healing phenotype, ultimately promoting epithelial repair and restoring barrier function in the lungs.

Through a series of experiments, this research demonstrated that Plet1 induces a regenerative program in lung epithelial cells, leading to increased proliferation and re-establishment of tight junction proteins crucial for barrier integrity. These effects emphasize the multifaceted nature of Plet1-mediated repair mechanisms. Furthermore, the interaction between macrophage-expressed Plet1 and the epithelium was investigated, with evidence suggesting that Plet1 acts in a soluble form in addition to its membrane-bound state, responding to signals released by injured epithelial cells.

Importantly, the therapeutic potential of Plet1 was highlighted through experiments in mice, where administration of recombinant Plet1 or transfer of Plet1-expressing macrophages conferred protection against influenza-induced lung injury. These findings suggest Plet1 as a promising therapeutic target for virus-induced lung injury, with potential applications beyond respiratory infections.

In conclusion, this study unveils the pivotal role of Plet1-mediated macrophage function in promoting lung epithelial repair, offering promising therapeutic avenues for combating virus-induced lung injury and advancing our understanding of immune responses to respiratory infections.

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