Ferroptosis in Low-Density Neutrophils of Tuberculosis Patients Suppresses Bactericidal Function.

OBJECTIVE: To analyse the immunological characteristics of low-density neutrophils (LDNs) in patients with tuberculosis (TB). METHODS: This study systematically characterized the immunological features of LDNs in active TB patients by comparing the proportion, phenotype and function of peripheral blood LDNs between healthy controls (HCs) and TB patients. Single-cell RNA sequencing analysis and quantitative PCR validation were performed. RESULTS: The proportion of LDNs was significantly increased in TB patients, exhibiting an enhanced effector phenotype but impaired migration and antibody-dependent functions. The direct bactericidal activity of LDNs against Mycobacterium bovis BCG was compromised. Single-cell sequencing analysis revealed significant upregulation of genes associated with ferroptosis and neutrophil extracellular trap (NETosis) formation pathways in TB patients' LDNs. Key ferroptosis-related genes HMOX1 and ACSL4 were upregulated, while GPX4 and FSP1 were downregulated, indicating increased susceptibility to ferroptosis. Functional intervention experiments demonstrated that treatment with the ferroptosis inhibitor Ferrostatin-1 enhanced the bactericidal capacity of LDNs against BCG. CONCLUSION: Ferroptosis and NETosis pathway activation in LDNs of TB patients leads to functional exhaustion and exacerbates immunopathology, providing new insights for immune intervention strategies in TB.