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Nat Immunol ; 25(6): 994-1006, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38671323

RESUMO

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal ß-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, ß-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.


Assuntos
Apolipoproteínas E , Lectinas Tipo C , Macrófagos Alveolares , Camundongos Endogâmicos C57BL , beta-Glucanas , Animais , Camundongos , Adaptação Fisiológica/imunologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Antígeno CD11b/metabolismo , Diferenciação Celular , Lectinas Tipo C/metabolismo , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo
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