Apolipoprotein E controls the development of monocyte-derived alveolar macrophages upon pulmonary inflammatory adaptation

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 uponenvironmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience

Transmission of trained immunity and heterologous resistance to infections across generations

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc

Author Correction: Transmission of trained immunity and heterologous resistance to infections across generations (Nature Immunology, (2021), 22, 11, (1382-1390), 10.1038/s41590-021-01052-7)

It has been called to our attention that our previous statistical analysis of our transcriptomic data of myeloid cell bone marrow progenitors in the offspring of exposed or non-exposed mice can be improved with a more stringent statistical analysis to identify differentially expressed genes (DEGs). The main improvement in the analysis would come if one filtered out lowly expressed genes or applied specific methods such as independent hypothesis weighting (IHW) or logFC shrinkage. We agree that those statistical models would reduce the number of false-positive results in the statistical test. In our published analysis—keeping in mind our biological question, a study on the transgenerational effect of acute infection—we applied a less stringent cutoff to maximize the number of genes to be further investigated, as we expected that relevant genes might have a relatively low fold change and expression. Having this in mind, we corroborated our results with several in vivo experiments supporting our findings. © 2023 The Author(s), under exclusive licence to Springer Nature America, Inc.

Transmission of trained immunity and heterologous resistance to infections across generations.

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections

Microglia as a critical player in both developmental and late-life CNS pathologies

Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer’s disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology—these benefits were abrogated by block of phagocytic function. In Alzheimer’s disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer’s disease