Ferroptosis-related genes are involved in asthma and regulate the immune microenvironment

Haixia Wang; Yuanmin Jia; Junlian Gu; Ou Chen; Shouwei Yue

doi:10.3389/fphar.2023.1087557

Ferroptosis-related genes are involved in asthma and regulate the immune microenvironment

Front Pharmacol. 2023 Feb 10:14:1087557. doi: 10.3389/fphar.2023.1087557. eCollection 2023.

Authors

Haixia Wang¹, Yuanmin Jia¹, Junlian Gu¹, Ou Chen¹, Shouwei Yue^{1

2}

Affiliations

¹ School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
² Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, Shandong, China.

Abstract

Background: Asthma was a chronic inflammatory illness driven by complicated genetic regulation and environmental exposure. The complex pathophysiology of asthma has not been fully understood. Ferroptosis was involved in inflammation and infection. However, the effect of ferroptosis on asthma was still unclear. The study was designed to identify ferroptosis-related genes in asthma, providing potential therapeutic targets. Methods: We conducted a comprehensive analysis combined with WGCNA, PPI, GO, KEGG, and CIBERSORT methods to identify ferroptosis-related genes that were associated with asthma and regulated the immune microenvironment in GSE147878 from the GEO. The results of this study were validated in GSE143303 and GSE27066, and the hub genes related to ferroptosis were further verified by immunofluorescence and RT-qPCR in the OVA asthma model. Results: 60 asthmatics and 13 healthy controls were extracted for WGCNA. We found that genes in the black module (r = -0.47, p < 0.05) and magenta module (r = 0.51, p < 0.05) were associated with asthma. CAMKK2 and CISD1 were discovered to be ferroptosis-related hub genes in the black and magenta module, separately. We found that CAMKK2 and CISD1 were mainly involved in the CAMKK-AMPK signaling cascade, the adipocytokine signaling pathway, the metal cluster binding, iron-sulfur cluster binding, and 2 iron, 2 sulfur cluster binding in the enrichment analysis, which was strongly correlated with the development of ferroptosis. We found more infiltration of M2 macrophages and less Tregs infiltration in the asthma group compared to healthy controls. In addition, the expression levels of CISD1 and Tregs were negatively correlated. Through validation, we found that CAMKK2 and CISD1 expression were upregulated in the asthma group compared to the control group and would inhibit the occurrence of ferroptosis. Conclusion: CAMKK2 and CISD1 might inhibit ferroptosis and specifically regulate asthma. Moreover, CISD1 might be tied to the immunological microenvironment. Our results could be useful to provide potential immunotherapy targets and prognostic markers for asthma.

Keywords: asthma; co-expression network analysis; ferroptosis; immune infiltration; tregs (regulatory T-cell).

Grants and funding

This work was supported by the National Natural Science Foundation of China (82172535 and 82172543), the Major Scientific and Technological Innovation Project in Shandong Province (2019JZZY011112), the Natural Science Foundation of Shandong Province (ZR2020MH006), and the Key Research and Development Program of Shandong Province (2019GSF108198).