Apolipoprotein E controls the development of monocyte-derived alveolar macrophages upon pulmonary 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, Wouter T'Jonck, A.H Gyorfi, H Hayer, X Yu, S Sheoran, A Al Jawazneh, S Chakarov, K Haendler, G.D BrownD.L Williams, L Bosurgi, J Distler, F Ginhoux, J Ruland, M Beyer, M Greter, Calum C Bain, A.I Vazquez-Armendariz, Manfred Kopf, J.L Schultze, A Schlitzer

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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+ AM). 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 M-CSF 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 post-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.
Original languageEnglish
JournalNature Immunology
DOIs
Publication statusPublished - 26 Apr 2024

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