Brain-lung axis regulation of MHC-II-associated neutrophils shapes pneumonia susceptibility after traumatic brain injury in aging

Aged patients with traumatic brain injury (TBI) are disproportionately vulnerable to pneumonia, yet links between aging and impaired pulmonary defense remain unclear. The brain–lung axis and neutrophil heterogeneity may play key roles, but defining protective neutrophil states and their neural–immune regulatory mechanisms in aged TBI remain incompletely understood. Single-cell RNA sequencing and flow cytometry are performed to characterize neutrophil heterogeneity in bronchoalveolar lavage fluid from young and aged TBI patients and mouse lung tissues. Young and aged mice are subjected to TBI and Klebsiella pneumoniae-induced pneumonia for in vivo functional studies. Optical clearing, immunofluorescence, fiber photometry, optogenetic and chemogenetic manipulations, adrenalectomy, and neutrophil-specific Nr3c1 conditional knockout are applied to dissect the neural circuit and molecular mechanisms. Antigen presentation, T-cell activation, and mitochondrial function assays are conducted for cellular functional validation. A randomized, placebo-controlled clinical trial is performed in 108 aged TBI patients to evaluate the prophylactic efficacy of oral mifepristone (200 mg/day for 14 days) against pneumonia. A distinct HLA-DRA+/CD74+ neutrophil population was identified after TBI, with this MHC-II-associated state appearing to be remodeled within the lung microenvironment rather than primarily generated in the bone marrow. Depletion of this protective subset is observed in aged TBI individuals and is closely associated with elevated pneumonia risk. Activation of the CeLSST–CeMGABA–PVNCRH neural circuit regulates excessive HPA‑axis glucocorticoid release. Aging was associated with increased NR3C1 expression on HLA‑DRA+/CD74+ neutrophils, contributing to mitochondrial dysfunction, impaired antigen presentation, and reduced pulmonary persistence. Treatment with mifepristone, an NR3C1 antagonist, restores the abundance and function of HLA‑DRA+/CD74+ neutrophils and enhances effector T‑cell responses. In the clinical trial, mifepristone showed a potential preventive effect against pneumonia in aged TBI patients without increasing adverse events. Our findings identify a stress–NR3C1–antigen-presenting neutrophil–T cell axis that contributes to age-biased pneumonia risk after TBI and identify mifepristone as a promising preventive therapeutic strategy. • Reduced abundance of a lung-enriched MHC-II-associated neutrophil population is associated with increased pneumonia susceptibility in aged TBI. • Higher NR3C1 expression in aged TBI neutrophils is negatively associated with MHC-II-associated neutrophil abundance. • CeLSST-CeMGABA-PVNCRH can activate the HPA axis, leading to high cortisol in aged TBI. • Mifepristone reduces pneumonia incidence after TBI and restores pulmonary immune responses through NR3C1 antagonism.