Th17 Cells Are Involved in Mouse Chronic Obstructive Pulmonary Disease Complicated with Invasive Pulmonary Aspergillosis
Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition characterized by persistent airflow limitation and chronic inflammation. In recent years, the incidence of COPD complicated with invasive pulmonary aspergillosis (IPA) has risen significantly, posing a severe threat to patient health. IPA, caused by the opportunistic fungus Aspergillus spp., is particularly dangerous in immunocompromised hosts. While COPD patients were once considered non-classical immunosuppressive hosts, recent evidence suggests that severe COPD patients are increasingly susceptible to IPA. The mortality rate for COPD patients with IPA is alarmingly high, ranging from 70% to 100%. Despite this, the mechanisms underlying the susceptibility to and high mortality of COPD complicated with IPA remain poorly understood.
The immune response is the primary defense mechanism against Aspergillus infection. Among the various T cell subsets involved in this response, T helper 17 (Th17) cells play a critical role. Th17 cells are known for their secretion of interleukin-17 (IL-17), a cytokine that is essential for host defense against fungal infections. Additionally, Th17 cells are implicated in the inflammatory processes associated with COPD. Given the dual role of Th17 cells in both COPD and fungal infections, this study aimed to investigate the function of Th17 cells in the context of COPD complicated with IPA.
To explore this, researchers established mouse models of COPD, IPA, and COPD combined with IPA (COPD+IPA) using male wild-type C57/BL6 mice. The levels of Th17 cells and their transcription factor, retinoic acid-related orphan receptor gamma t (RORγt), were measured using flow cytometry. Serum levels of IL-17 and IL-23 were detected using enzyme-linked immunosorbent assay (ELISA). Additionally, the role of IL-17 was further investigated using IL-17 knockout (KO) mice.
The study revealed several key findings. First, the COPD+IPA group exhibited higher levels of blood RORγt and serum IL-17 compared to the COPD group. However, there were no significant differences in blood and lung levels of Th17 cells, lung levels of RORγt, or serum IL-23 between these two groups. When compared to the IPA group, the COPD+IPA group showed lower levels of blood and lung Th17 cells, as well as reduced serum IL-23 and IL-17. Notably, the Aspergillus load in IL-17 KO COPD+IPA mice was nearly twice that of COPD+IPA mice, indicating a protective role of IL-17 against fungal infection.
The establishment of the COPD model was confirmed through weight changes, lung function parameters, and histological analysis. Mice in the COPD and COPD+IPA groups exhibited significant weight loss compared to control and IPA groups. Lung function tests revealed that COPD mice had higher pulmonary compliance and airway resistance but lower elastic resistance compared to control mice. Histological examination showed structural damage in the lungs of COPD mice, including incomplete mucosal epithelium, shorter bronchial cilia, and alveolar wall thinning or rupture. In contrast, IPA mice exhibited necrosis and Aspergillus hyphal growth in the lungs, while COPD+IPA mice displayed a combination of these features.
Flow cytometry analysis demonstrated that the COPD+IPA group had higher blood RORγt levels than the COPD group, but similar levels of blood and lung Th17 cells. Compared to the IPA group, the COPD+IPA group had significantly lower levels of blood and lung Th17 cells, as well as reduced serum IL-23 and IL-17. These findings suggest that Th17 cells may be involved in the pathogenesis of COPD combined with IPA, but their function is partially impaired in this context.
The role of IL-17 was further elucidated using IL-17 KO mice. The Aspergillus load in IL-17 KO COPD+IPA mice was significantly higher than in COPD+IPA mice, indicating that IL-17 plays a protective role against fungal infection. This finding aligns with previous studies showing that IL-17-deficient mice have increased fungal loads after invasive fungal infections, likely due to impaired neutrophil recruitment and cytokine expression.
The study also highlighted the potential mechanisms underlying the ineffective immune response in COPD. Chronic inflammation in COPD may lead to defective immune responses, including T cell depletion and impaired cytokine production. This immune dysfunction could contribute to the increased susceptibility to IPA in COPD patients. Additionally, the study suggested that the Th17 cell-associated immune pathway may be involved in cytokine production and secretion in the pathogenesis of COPD combined with IPA, although Th17 cells do not effectively respond to Aspergillus infection in the context of COPD.
In conclusion, this study provides valuable insights into the role of Th17 cells and IL-17 in COPD complicated with IPA. The findings suggest that Th17 cells are involved in the immunopathological process of this compound disease, but their function is partially inhibited. IL-17, however, plays a protective role against fungal infection, as evidenced by the increased Aspergillus load in IL-17 KO mice. These results underscore the importance of the Th17 cell-associated immune pathway in the pathogenesis of COPD combined with IPA and highlight the potential for therapeutic interventions targeting this pathway.
Further studies, including clinical trials, are necessary to validate these findings and explore potential therapeutic strategies. Understanding the mechanisms underlying the immune dysfunction in COPD complicated with IPA could lead to improved treatments and better outcomes for patients with this severe and often fatal condition.
doi.org/10.1097/CM9.0000000000001183
Was this helpful?
0 / 0