Metabolic signals guide the formation of lung macrophages
A study published in The Journal of Experimental Medicine reveals how circulating monocytes detect tissue signals that guide their differentiation into lung macrophages. The work was led by Tim Willinger (Karolinska Institute), Bart Lambrecht (VIB-UGent) and Thomas Marichal (GIGA Institute, WEL Research Institute), and involved an international collaboration of scientists studying immune cell development in the lung.
Macrophages are essential immune cells that reside in tissues and maintain organ health. In the lungs, they occupy specialized niches in the interstitial tissue and the alveoli, where they help control inflammation and protect against infection. When these resident macrophages are lost, for example during injury or disease, circulating monocytes are recruited from the blood and must differentiate locally to replenish the macrophage population. However, the signals guiding this process have remained poorly understood.
In this study, the researchers discovered that monocytes rely on the receptor GPR183 to sense metabolic signals in the lung microenvironment, allowing them to locate macrophage niches and differentiate properly. Specifically, the team showed that lung fibroblasts produce oxysterols, which are cholesterol-derived metabolites, that act as instructive signals for incoming monocytes. These metabolites activate the receptor GPR183 on monocytes, positioning them near fibroblasts and promoting their differentiation into lung macrophages.
Using advanced mouse models, single-cell RNA sequencing and imaging approaches, the study demonstrated that GPR183 is expressed by monocytes and developing macrophages during the repopulation of lung macrophage niches. Once macrophages are fully established in the tissue, the receptor is downregulated, indicating that GPR183 functions primarily during the differentiation phase.
“Our findings show that metabolic signals produced within lung tissue help guide monocytes toward macrophage niches and instruct their differentiation” explains Thomas Marichal. “Understanding how these local cues shape immune cell development may open new strategies to modulate macrophage responses in lung diseases.”
These findings reveal a new mechanism by which metabolic signals in tissue niches instruct immune cell fate. Because GPR183 is a G-protein-coupled receptor, a class of proteins frequently targeted by drugs, the pathway may represent a promising therapeutic target to modulate macrophage responses in lung diseases.
Thomas Marichal is affiliated at the WEL Research Institute (WelRI), the project was funded by the European Research Council (ERC) and the Baillet Latour Fund.
Reference
Sensing of metabolic signals via GPR183 promotes occupation of lung macrophage niches by monocytes.
Bub L, Evren E, Verwaerde S, Ruscitti C, Vanneste D, Ghosh P, Gao Y, Sleiers N, Deng R, López Montes M, Howley K, La Rocca R, Niehrs A, Glaros V, Reina-Campos M, Dahlen B, Smed-Sörensen A, Lund H, Kreslavsky T, Björkström NK, Reboldi A, Bossios A, Marichal T, Lambrecht BN, Willinger T. J Exp Med. 2026 Apr 6;223(4):e20252667. doi: 10.1084/jem.20252667. Epub 2026 Mar 3. PMID: 41774079 Free PMC article.
