Sensing of metabolic signals via GPR183 promotes occupation of lung macrophage niches by monocytes
Monocytes populate tissues when local niches are depleted of tissue-resident macrophages, yet the tissue-derived signals controlling monocyte-to-macrophage differentiation are largely undefined. Here, we discovered that the oxysterol receptor GPR183 positions monocytes to sense niche signals that induce lung macrophage differentiation. We found that interstitial macrophages that continuously turn over express the oxysterol receptor GPR183, whereas alveolar macrophages that derive from embryonic progenitors and slowly turn over did not. Models of conditional tissue-resident macrophage depletion showed that newcomer monocyte-derived macrophages expressed GPR183 along their differentiation trajectory. Recruited GPR183+ monocytes interacted with fibroblasts and lack of GPR183 caused defective lung macrophage differentiation. Single-cell RNA analysis over time identified lung fibroblasts as the source of the GPR183 ligand 7α,25-dihydroxycholesterol in the empty niche. Our findings identify oxysterols as instructive signals for tissue-resident macrophage development from monocytes.
Authors
- Cecilia Ruscitti (ORCID: https://orcid.org/0000-0002-3131-8623)
- Harald Lund (ORCID: https://orcid.org/0000-0001-8046-0805)
- Natalie Sleiers
- Maria Reina-Campos (ORCID: https://orcid.org/0000-0003-2417-5289)
- Tim Willinger (ORCID: https://orcid.org/0000-0002-8720-7199)
- Taras Kreslavsky (ORCID: https://orcid.org/0000-0002-6672-1914)
- Barbro Dahlén (ORCID: https://orcid.org/0000-0003-3803-9034)
- Vassilis Glaros (ORCID: https://orcid.org/0000-0001-6211-9515)
- Annika Niehrs (ORCID: https://orcid.org/0000-0002-2190-4346)
- Apostolos Bossios (ORCID: https://orcid.org/0000-0002-0494-2690)
- Raphaël La Rocca (ORCID: https://orcid.org/0000-0003-3388-3041)
- Yu Gao (ORCID: https://orcid.org/0000-0002-8696-442X)
- Stijn Verwaerde (ORCID: https://orcid.org/0000-0002-1398-8746)
- Anna Smed‐Sörensen (ORCID: https://orcid.org/0000-0001-6966-7039)
- Elza Evren (ORCID: https://orcid.org/0000-0002-5656-4417)
- Domien Vanneste (ORCID: https://orcid.org/0000-0003-0148-8397)
- Thomas Marichal (ORCID: https://orcid.org/0000-0003-1688-6291)
- Andrea Reboldi (ORCID: https://orcid.org/0000-0003-1137-6292)
- Kelsey Howley
- Pia Ghosh
- Marta López Montes
- Bart N. Lambrecht
- Laura Bub
- Rong Deng
Institutions
- HOGENT University of Applied Sciences and Arts (BE)
- Karolinska University Hospital (SE)
- University of Liège (BE)
- University of Massachusetts Chan Medical School (US)
- Ghent University Hospital (BE)
- Karolinska Institutet (SE)
- Ghent University (BE)
- VIB-UGent Center for Inflammation Research (BE)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1084/jem.20252667
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.43
Funders
- Yale University
- Fonds De La Recherche Scientifique - FNRS
- Fonds Wetenschappelijk Onderzoek
- Lunds Universitet
- Hjärt-Lungfonden
- Karolinska Institutet
- Vetenskapsrådet
- Walloon excellence in life sciences and biotechnology
- National Institutes of Health
- Center for Innovative Medicine