Sensing of metabolic signals via GPR183 promotes occupation of lung macrophage niches by monocytes.

Summary

Using depletion models and single-cell transcriptomics, the authors show that fibroblast-derived 7α,25-dihydroxycholesterol engages GPR183 on recruited monocytes, positioning them to occupy vacated lung macrophage niches and differentiate into interstitial macrophages. Loss of GPR183 impairs this differentiation, establishing oxysterols as instructive niche cues for tissue-resident macrophage development.

Key Findings

• Interstitial lung macrophages (but not embryonically derived alveolar macrophages) express GPR183.
• Following niche depletion, newcomer monocyte-derived macrophages upregulate GPR183 along their differentiation trajectory.
• Fibroblasts supply 7α,25-dihydroxycholesterol in empty niches, engaging GPR183 to instruct monocyte-to-macrophage differentiation.
• GPR183 deficiency causes defective lung macrophage differentiation and niche occupation.

Clinical Implications

Therapeutically tuning oxysterol-GPR183 signaling could enhance repopulation of beneficial macrophages in lung injury, fibrosis, or infection, or conversely restrict maladaptive macrophage differentiation in chronic lung disease.

Limitations

• Preclinical models limit direct extrapolation to human therapeutic modulation
• No interventional pharmacology to test modulation of GPR183 in vivo disease models

Future Directions

Evaluate pharmacologic agonists/antagonists of GPR183 in lung injury, infection, and fibrosis models; map oxysterol gradients in human lung disease; and assess translational biomarkers of GPR183 activity.