Hypobaric hypoxia can lead to an increase in lung dendritic cells and promote T-cell immunosuppression, thereby preventing the excessive progression of high-altitude pulmonary edema.

Abstract

BACKGROUND: More and more studies have shown that the immune system regulates the body's response to hypoxic stress. Immune dysregulation may increase vascular permeability, leading to edema and tissue damage, thereby causing high-altitude pulmonary edema (HAPE). Here, we found an increase in lung dendritic cells (DCs) in rat and mouse models of HAPE, but its specific role in HAPE remains unclear. METHODS: In this study, the function of rat lung DCs and its impact on T cells were analyzed through single-cell sequencing, flow cytometry andco-culture. Then, we confirmed its effects on DCs and T cells by intraperitoneal injection of TNF-α or by using TNF-α -deficient mice. Finally, we evaluated the role of CD4T cells in the progression of HAPE by eliminating CD4 in mice with neutralizing antibodies. RESULTS: We demonstrated that hypobaric hypoxia (HH) induced the recruitment of pulmonary DCs in rats and promoted the immunosuppression of T cells (especially CD4T cells). By injecting TNF-α into rats, we found that the number of DC and CD4CD25T cells in the lung of HH rats slightly decreased. Interestingly,injection of TNF-α actually led to the production of less TNF-α by CD4T cells in the lung of HH rats. In the HAPE mouse model, the proportion and the number of DC in the lung of TNF-α -deficient mice were significantly increased, and the level of IL-6 production was significantly decreased. Furthermore, the proportion of CD4CD25T cells in the lung of TNF-α -deficient mice increased significantly. By eliminating CD4 in mice with neutralizing antibodies, we found that CD4T cells play a protective role in HAPE. CONCLUSIONS: Our results indicate that hypoxia induces the recruitment of DCs in the lung and mediates the differentiation of T cells into immunosuppressive phenotypes in HAPE rat and mouse models, thereby delaying the progression of HAPE. These findings highlight the potential approach of using immune regulation as a treatment for HAPE.