EC Pulmonology and Respiratory Medicine

Asthma is a heterogeneous chronic inflammatory disease characterized by persistent airway inflammation, epithelial injury, and structural remodeling. While macrophages are among the most abundant immune cells in the lung, their functional diversity in asthma remains incompletely understood. Recent advances in single-cell transcriptomics have identified previously unrecognized macrophage subsets expressing Placenta Expressed Transcript 1 (PLET1), a molecule traditionally associated with epithelial regeneration and tissue repair. Emerging evidence from lung injury and fibrotic disease models suggests that PLET1-expressing macrophages may participate in tissue repair, extracellular matrix remodeling, and immune regulation. However, their contribution to asthma has received little attention. This opinion article proposes that PLET1-expressing macrophages represent an overlooked component of airway immunity that may integrate epithelial repair with inflammatory responses during asthma progression. Potential mechanisms through which these cells could influence airway remodeling, type 2 inflammation, and disease resolution are discussed, together with the major unanswered questions in the field. It is further proposed that investigating PLET1-expressing macrophages may identify novel biomarkers and therapeutic targets, thereby advancing precision medicine strategies for asthma.

Keywords: Asthma; Placenta Expressed Transcript 1 (PLET1); Type 2 Inflammation

1. Lumeng CN. “Lung macrophage diversity and asthma”. Annals of the American Thoracic Society 1 (2016): S31-S24.
2. Morales-Nebreda L., et al. “The heterogeneity of lung macrophages in the susceptibility to disease”. European Respiratory Review137 (2015): 505-509.
3. Aran D., et al. “Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage”. Nature Immunology 2 (2019): 163-172.
4. Pervizaj-Oruqaj L., et al. “Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia”. Nature Communications 1 (2024): 87.
5. Depreter MG., et al. “Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells”. Proceedings of the National Academy of Sciences of the United States of America 3 (2008): 961-966.
6. Russell RA., et al. “The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma”. European Respiratory Journal4 (2024): 2301397.
7. Misharin AV., et al. “Bronchoalveolar macrophage heterogeneity in the healthy lung is defined by cellular lineage and not activation state”. American Journal of Respiratory and Critical Care Medicine6 (2013): 728-735.
8. Morse C., et al. “Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis”. European Respiratory Journal 2 (2019): 1802441.
9. Jaitin DA., et al. “Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner”. Cell3 (2019): 686-698.e14.