^† These authors contributed equally: Julian Better and Mohammad Estiri
Senior authors: Ulrich Matt and Susanne Herold

In pioneering research, scientists have uncovered why patients recovering from acute lung injury may become susceptible to life-threatening secondary bacterial infections. Alveolar macrophages (AMs), the resident immune cells responsible for combating bacteria and orchestrating inflammation in the lung, undergo a functional transformation during the healing process, prioritizing inflammation resolution over effective bacterial defense.

The study, conducted by the research group led by Ulrich Matt and Susanne Herold, and recently published in the renowned journal *Science Immunology*, reveals that AMs are less capable of mounting an effective immune response to bacteria during the resolution of inflammation. The process is fueled by neutrophil-derived myeloperoxidase (MPO), which enhances canonical glutaminolysis via mitochondrial uncoupling protein-2 (UCP2). This immunometabolic reprogramming decreases the production of mitochondrial reactive oxygen species (mtROS), which are crucial for bacterial killing and triggering an inflammatory response.

Julian Better and Mohammad Estiri, the study's lead authors, explain, "The ability of AMs to switch between phenotypes is vital for recovering from lung injuries. However, our research shows that while AMs clear dying neutrophils during the resolution of inflammation, termed efferocytosis, they undergo an immunometabolic fate decision in an MPO-dependent manner that inadvertently guides them towards resolving inflammation at the expense of fighting off bacteria."

Principal investigator and senior author Ulrich Matt further notes, "Interestingly, when alveolar macrophages performed efferocytosis on cells other than neutrophils, they transitioned to an anti-inflammatory state while preserving their antibacterial capabilities," coining and highlighting the concept of cell type-specific efferocytosis.

This discovery not only sheds light on the mechanisms behind lung infection vulnerability but also has broader implications. The same phenomenon was observed in extrapulmonary macrophages in mice and human alveolar macrophages, suggesting a conserved biological mechanism across species.

Targeting the immunometabolic hub UCP2 in different models of secondary bacterial infection after acute lung injury significantly improved the survival of mice in vivo. The researchers are hopeful that these insights will pave the way for developing new therapeutic strategies aimed at balancing inflammation resolution and bacterial defense in the lungs.

Find the full article here: https://www.science.org/stoken/author-tokens/ST-2605/full