This study investigated how A. fumigatus infection, based on altered TLR2 ubiquitination in the context of COPD, further activates the NLRP3/Caspase-1/GSDMD-N-mediated pyroptosis pathway, thereby exacerbating pulmonary inflammatory responses. A COPD model in male C57BL/6J mice was established using whole-body cigarette smoke exposure, followed by acute exacerbation through respiratory instillation of A. fumigatus spores. Western blotting was used to quantify the expression of pyroptosis-related proteins (Caspase-1, NT-GSDMD, and NLRP3) and TLR2. Ubiquitination assays were used to evaluate TLR2–Ub binding, and ELISA assays were used to measure inflammatory cytokine levels (IL-8, IL-6, TNF-α, and IL-10). Modulators of TLR2 ubiquitination were employed to evaluate their impact on pyroptosis and the inflammatory response. The lung tissues of COPD mice infected with A. fumigatus showed significantly elevated TLR2 protein accumulation and pyroptosis-related protein expression. Alveolar macrophages showed reduced viability and increased LDH release, indicating enhanced cellular damage. Pro-inflammatory cytokines (IL-8, IL-6, and TNF-α) were markedly upregulated in bronchoalveolar lavage fluid and cell culture supernatants, whereas anti-inflammatory IL-10 levels were decreased. Notably, TLR2–Ub binding was reduced in infected COPD mice, suggesting increased TLR2 stability. Treatment with TLR2 ubiquitination modulator attenuated the expression of pyroptosis-related proteins, suppressed the release of inflammatory cytokines, improved cell survival, and mitigated cellular injury. This study elucidated the regulatory role of TLR2 ubiquitination in A. fumigatus-induced pyroptosis and inflammation during COPD exacerbation. Targeting TLR2 ubiquitination may be a novel therapeutic strategy for managing exacerbations of Aspergillus-associated COPD. Future studies should investigate the translational potential of TLR2 ubiquitination inhibitors for the treatment of COPD.
Gou et al. (Sat,) studied this question.