An ILC2-chitinase circuit restores lung homeostasis after epithelial injury
Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.
Authors
- Roberto Efraín Díaz (ORCID: https://orcid.org/0000-0002-1172-9919)
- Ahmed O. Hassan (ORCID: https://orcid.org/0000-0002-9638-1260)
- J. Michael White (ORCID: https://orcid.org/0000-0001-5110-6567)
- Sanjana Reddy
- James S. Fraser (ORCID: https://orcid.org/0000-0002-5080-2859)
- Steven J. Van Dyken (ORCID: https://orcid.org/0000-0002-9787-0883)
- Haerin Jung (ORCID: https://orcid.org/0000-0003-2209-8638)
- Richard M. Locksley (ORCID: https://orcid.org/0000-0002-5468-6867)
- Michael Diamond (ORCID: https://orcid.org/0000-0002-8791-3165)
- Summer Rucknagel
- Do-Hyun Kim (ORCID: https://orcid.org/0000-0003-0160-3092)
- Yilin Wang (ORCID: https://orcid.org/0000-0002-8261-7439)
- Baoling Ying
- Emma S. Winkler (ORCID: https://orcid.org/0000-0001-8510-1385)
- Lauryn Mosby
Institutions
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1126/sciimmunol.adl2986
- Citations
- 5
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- Washington University in St. Louis
- Alvin J. Siteman Cancer Center
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute
- National Center for Research Resources