A Dual role of alveolar macrophage in driving host defense and pulmonary immunopathology during hypervirulent Acinetobacter baumannii pneumonia.

Hypervirulent Acinetobacter baumannii (hvAB) is a leading cause of refractory bacterial pneumonia. However, cellular and molecular mechanisms underlying hvAB-induced host protection and pulmonary immunopathology remain poorly understood. Here, we performed longitudinal single-cell RNA sequencing on lung tissues in a mouse model of hvAB pneumonia and delineated a time-dependent innate immune landscape of the infected lung. Functional experiments demonstrated that neutrophil (Neu) was dispensable for hvAB clearance but exacerbated acute lung injury through Neu extracellular traps formation (NETosis). Lung-resident CD11b- alveolar macrophage (AM) was indispensable for host defense and for restraining early Neu infiltration. Upon hvAB infection, CD11b- AM underwent phenotypic switching to a hyper-activated CD11b+ pro-inflammatory state, characterized by markedly decreased phagocytic activity and robustly enhanced IL-1β secretion. Mechanistically, IL-17A acted as a key pathogenic mediator by driving excessive Neu recruitment, aberrant NETosis, and progressive AM loss. IL-17A was predominantly produced by group 3 innate lymphoid cell (ILC3) in an IL-1β-dependent manner. Collectively, our study defined a critical pathogenic AM-ILC3-Neu axis and highlighted a paradoxical dual role of AM in driving host defense and pulmonary immunopathology through dynamic phenotypic switching. We suggested that targeting AM phenotypic plasticity represented a promising therapeutic strategy to alleviate excessive immunopathology while preserving protective host defense during hvAB pneumonia.