Atypical pericapillary Ly6G⁺Nur77⁺ macrophages initiate type-2 immune responses to allergens in the mouse lung

  • Nat Commun. 2026 Jan 22;17(1):1946. doi: 10.1038/s41467-026-68652-5.
Audrey Meloun  1  2 ,  Holly Bachus  3 ,  Crystal Lewis  4 ,  Brittany Dulek  5 ,  Shivangi Dave  3  6 ,  Dave Durell Hill  7 ,  Gabriela Pessenda  8 ,  Jose Carlos Gonzalez  9 ,  P'ng Loke  8 ,  Alexander F Rosenberg  7 ,  Beatriz León  10
Affiliations
  • 1. Innate Cells and Th2 Immunity Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 3. Adaptive Immunity and Immunoregulation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 4. Department of Pathology-Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 5. Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 6. Department of Medicine-Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 7. Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 8. Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 9. Department of Neurobiology and McKnight Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 10. Innate Cells and Th2 Immunity Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [email protected].
PMID: 41571657 DOI: 10.1038/s41467-026-68652-5
Abstract

The mechanisms of airway allergen sensing and type 2 immune response initiation remain poorly understood. Using a mouse house dust Mite (HDM)-induced allergic airway model, we identify a population of lung macrophages located close to alveolar capillaries that express Ly6G and the nuclear receptor Nr4a1/Nur77. These atypical Ly6G+Nur77+ macrophages preferentially capture airway-delivered allergens and play an important role in initiating HDM-driven T helper type 2 (Th2) responses. They sense the major HDM allergen, the cysteine protease Der p 1, via Protease-activated Receptor 2 (PAR2), and their activation and accumulation require both PAR2 and Nr4a1/Nur77. These Ly6G+Nur77+ macrophages regulate the migration of conventional migratory dendritic cells (mDCs) to draining mediastinal lymph nodes (mLNs) through cysteinyl leukotriene (CysLT) production, which enhances mDC migration toward CCL21 for T cell priming. Inhibiting CysLT biosynthesis reduces mDC migration and dampens Th2 allergic responses, highlighting possible therapeutic avenues in type 2 immunity.

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