IL-17RA Drives COPD Progression by Activating Dual Pyroptosis Pathways in Alveolar Epithelial Cells
核心洞察
Knockout of IL-17RA (搜索) in alveolar type II epithelial cells significantly alleviated cigarette smoke-induced COPD (搜索) progression in mice, with improved lung function and reduced inflammatory cell infiltration.
IL-17RA (搜索) activates both the canonical NLRP3 (搜索)/Caspase1/GSDMD (搜索) pyroptosis pathway and the non-canonical NF-κB/GSDME (搜索) pathway, while IL-17A (搜索) binding triggers only the canonical pathway.
In the COPD (搜索) mouse model, IL-17RA (搜索) knockout reduced pyroptosis-related inflammatory cytokines IL-1β, IL-6, and IL-18 in serum and bronchoalveolar lavage fluid.
Chronic obstructive pulmonary disease (COPD (搜索)) remains the third leading cause of death worldwide, yet the high incidence and mortality rates have not substantially improved despite advances in diagnosis and treatment. A new study published in the Journal of Inflammation Research now identifies interleukin-17 receptor A (IL-17RA (搜索)) on alveolar type II (AT2) epithelial cells as a critical driver of pyroptosis—a pro-inflammatory form of programmed cell death—that accelerates COPD progression, revealing a potential precision therapeutic target.
IL-17RA (搜索) Knockout Alleviates COPD (搜索) Pathology in Mouse Models
Researchers at Zunyi Medical University employed a cigarette smoke exposure model in mice with a conditional knockout of IL-17RA (搜索) specifically in AT2 cells (IL-17RA−/− SFPTC-cre(+) mice). After 24 weeks of chronic cigarette smoke exposure, IL-17RA−/− mice demonstrated marked improvements across multiple disease parameters compared to wild-type controls.
Lung tissue from IL-17RA (搜索)−/−+CS mice exhibited partial restoration of pink coloration and elastic properties, in contrast to the grayish-white, inelastic lungs observed in the CS group. Histological analysis via HE staining revealed contracted alveolar cavities, structural reconstruction of alveolar septa, and markedly reduced inflammatory cell infiltration in the knockout group. Masson's staining further showed reduced collagen deposition. CT imaging confirmed that the increased anterior-posterior thoracic diameters seen in CS-exposed wild-type mice were significantly improved in IL-17RA−/− animals.
Pulmonary function testing demonstrated that forced expiratory volume in the first second/forced vital capacity (FEV1/FVC), peak expiratory flow (PEF), maximal voluntary ventilation (MV), and dynamic lung compliance (CDyn)—all significantly decreased in the CS group—showed significant recovery in IL-17RA (搜索)−/− mice.
Dual Pyroptosis Pathway Activation Through IL-17RA (搜索)
The study elucidated that IL-17RA (搜索) promotes COPD (搜索) progression by activating two distinct pyroptosis pathways. Immunohistochemistry and western blot analyses showed that N-GSDMD (搜索) and GSDME (搜索) protein expression were significantly elevated in the CS group, while IL-17RA−/− mice exhibited markedly reduced levels of both proteins.
Transmission electron microscopy provided direct morphological evidence: AT2 cells in the CS group displayed characteristic pyroptotic features including irregular nuclei, dilated rough endoplasmic reticulum, significant cell membrane perforation, and cytoplasmic contents spilling into the alveolar lumen. In IL-17RA (搜索)−/− mice, nuclear and cell membranes remained largely intact, with only a few small perforations observed.
Mechanistically, the researchers demonstrated that cigarette smoke extract (CSE) activates IL-17RA (搜索) to trigger the canonical NLRP3 (搜索)/Caspase1/GSDMD (搜索) pathway and the non-canonical NF-κB/GSDME (搜索) pathway. "IL-17RA is a key protein in the pathway of pyroptosis activated by cigarette smoke, providing new insights into the critical proteins involved in the pyroptosis process induced by cigarette smoke," the authors stated.
ELISA results showed that pyroptosis-related inflammatory cytokines IL-1β, IL-6, and IL-18 were significantly elevated in both serum and bronchoalveolar lavage fluid of CS-exposed mice, while IL-17RA (搜索)−/− mice exhibited significantly reduced levels.
IL-17A (搜索) Activates Only the Canonical Pathway
Further investigation using recombinant IL-17A (搜索) protein revealed an important mechanistic distinction: while IL-17A binds to IL-17RA (搜索) and activates the NLRP3 (搜索)/Caspase1/GSDMD (搜索) canonical pyroptosis pathway in a concentration-dependent manner, it does not activate the NF-κB/GSDME (搜索) non-canonical pathway. The addition of NLRP3-specific inhibitor MCC950 and Caspase-1-specific inhibitor VX-765 confirmed that IL-17A-driven pyroptosis proceeds exclusively through the canonical route.
"We speculate that the activation of the NF-κB/GSDME (搜索) non-canonical pathway by IL-17RA (搜索) is not mediated by IL-17A (搜索) but may involve other inflammatory factors," the researchers noted, highlighting the distinct roles of IL-17A and IL-17RA in COPD (搜索) pathogenesis.
In Vitro Validation in Human AT2 Cells
In immortalized human AT2 cell lines, exposure to 8% CSE for 24 hours significantly increased expression of NLRP3 (搜索), N-GSDMD (搜索), GSDME (搜索), IL-1β, IL-17A (搜索), IL-18, and TNF-α. Lentiviral knockdown of IL-17RA (搜索) reversed these changes, with LDH release and PI/Hoechst 33342 staining confirming reduced pyroptosis. Notably, while GSDMD cleavage was regulated by IL-17RA, total GSDMD protein levels remained unchanged, indicating that IL-17RA controls the post-translational processing rather than transcription of GSDMD.
Study Limitations and Future Directions
The authors acknowledged several limitations: all experiments used male animals and cells, leaving sex-specific differences unevaluated; the precise mechanisms by which IL-17RA (搜索) activates NLRP3 (搜索) and NF-κB remain incompletely understood; and validation in COPD (搜索) patients is still required. "We maintain a conservative stance regarding the translational and therapeutic implications of our findings," the researchers cautioned, while emphasizing that the study provides an experimental basis for precisely targeting IL-17RA in AT2 cells for COPD treatment.