Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

H. Theobald, D. A. Bejarano, N. Katzmarski, J. Haub, J. Schulte-Schrepping, J. Yu, K. Bassler, A. L. Ament, C. Osei-Sarpong, F. Piattini, L. Vornholz, W. T’Jonck, A. H. Györfi, H. Hayer, X. Yu, S. Sheoran, A. Al Jawazneh, S. Chakarov, K. Haendler, G. D. BrownD. L. Williams, L. Bosurgi, J. H.W. Distler, F. Ginhoux, J. Ruland, M. D. Beyer, M. Greter, C. C. Bain, A. I. Vazquez-Armendariz, M. Kopf, J. L. Schultze, A. Schlitzer

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Résumé

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 β-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, β-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.

langue originaleAnglais
Pages (de - à)994-1006
Nombre de pages13
journalNature Immunology
Volume25
Numéro de publication6
Les DOIs
étatPublié - 1 juin 2024
Modification externeOui

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