Chitinase variants establish environmental inflammatory lung conditioning

Abstract

Environmental particulate exposure contributes to the severity and persistence of numerous acute and chronic lung diseases, including asthma, viral pneumonia, acute respiratory distress syndrome, and pulmonary fibrosis. Chitin, a highly abundant environmental polysaccharide present in fungi, insects, and mites, is continuously encountered at mucosal barrier surfaces and functions as an immunostimulatory particulate substrate within the respiratory tract. Acidic mammalian chitinase (AMCase; CHIA) is an evolutionarily conserved mammalian enzyme that degrades chitin-containing particles and regulates inflammatory responses at barrier tissues. Common human CHIA polymorphisms reduce AMCase enzymatic activity and are associated with asthma susceptibility; however, the physiologic consequences of these variants in vivo remain poorly understood. To investigate how common human AMCase variants influence environmental chitin processing and inflammatory disease susceptibility, humanized mouse models encoding linked human CHIA polymorphisms were generated using CRISPR/Cas9-mediated gene editing. Humanized AMCase (hChia) mice exhibited reduced chitinase activity against both soluble and insoluble chitin substrates in vivo without substantial alterations in AMCase protein expression. Impaired chitin degradation in hChia mice was associated with chronic inflammatory conditioning within the lung characterized by alveolar macrophage priming, γδ T cell activation, and altered epithelial remodeling responses. Environmental chitin exposure contributed to this steady-state inflammatory conditioning, as low-chitin housing attenuated inflammatory priming phenotypes in hChia mice. Reduced AMCase activity further enhanced susceptibility to environmentally driven inflammatory disease. In models of house dust mite-induced allergic airway inflammation, hChia mice developed increased eosinophilic inflammation, elevated IL-1β production, enhanced γδ T cell activation, and augmented CD4⁺ T cell responses. Following influenza A virus infection, hChia mice exhibited altered epithelial remodeling and exaggerated inflammatory responses during post-viral allergen challenge. In bleomycin-induced pulmonary fibrosis, hChia mice demonstrated increased early inflammatory injury, worsened fibrotic remodeling, and increased mortality following inflammatory exacerbation. Together, these findings identify environmental chitin processing as a regulator of lung inflammatory tone and demonstrate that common human AMCase variants shape susceptibility to allergic, viral-associated, and fibrotic lung disease through environmentally driven immune conditioning pathways. Translational analyses of human airway samples demonstrated the presence of chitin within the injured human lung and identified associations between airway chitin accumulation, alveolar hemorrhage, and excess airway protein accumulation. Collectively, these studies define a gene-environment interaction in which common human AMCase variants regulate environmental particle processing and establish inflammatory susceptibility within the lung.