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Epigenetic reprogramming of macrophages in chronic diseases

Hey, Joschka

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Macrophages are innate immune cells and maintain a prominent role in host defense, tissue homeostasis, and immune response. Diverse macrophage populations reside in most tissues, and their immense plasticity, mediated through distinct gene-regulatory and epigenetic mechanisms, allows macrophages to react to an altered microenvironment quickly. The adaptation of macrophages occurs both in physiological and pathological conditions, making them a key determinant of many inflammatory and non-inflammatory diseases. The clear link between disease progression, epigenetic reprogramming, and functional adaptations is frequently unknown. This doctoral thesis aims to comprehensively characterize the epigenomes and coinciding transcriptional patterns of macrophages and monocytes in muco-obstructive lung disease and breast cancer, two chronic diseases with a significant health burden worldwide.

The first part of this doctoral thesis addresses the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AMs). Mucus obstruction and chronic airway inflammation characterize many chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Utilizing the Scnn1b-transgenic mouse model of muco-obstruction, we determined epigenetically regulated and differentially activated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Enhanced activation of AMs in muco-obstructive lungs was validated via single-cell surface marker expression. Ex vivo stimulation of AMs from healthy lungs with mucus per se induced gene expression changes, reminiscent of those observed in AMs from muco-obstructed lungs. Furthermore, Scnn1b-transgenic AMs showed functional impairment in efferocytosis and phagocytosis capacities. In addition, excessive inflammatory responses upon lipopolysaccharide stimulation, mediated through epigenetic priming by enhanced activity and expression of Irf1, were revealed.

Collectively, these results depict that mucostasis induces epigenetic reprogramming of AMs, leading to phenotypic and functional changes favoring tissue damage and disease progression. Targeting epigenetically altered AMs may support therapeutic approaches in patients with muco-obstructive lung disease.

The second part of this doctoral thesis examines the epigenetic reprogramming of tumor-associated macrophages (TAMs) by breast cancer. The development of breast cancer induces the accumulation of TAMs within the tumor microenvironment, which acquire a distinct phenotype and tumor-promoting functions. Yet, the epigenetic mechanism underlying the differentiation of TAMs from bone marrow-derived monocytes remains largely unknown.

Using the 4T1 orthotopic mouse model, we showed that the presence of breast cancer significantly altered the DNA methylation landscape of macrophages and monocytes. The cancer-specific methylome of TAMs was dissected in DNA methylation patterns originating from bone marrow-derived monocytes, as well as TAM-specific alterations. These modifications in the DNA methylation landscape coincided with a cancer-specific transcriptome enriched in aggressive breast cancer subtypes and associated with shorter cancer-specific survival. Utilizing a single-cell gene expression atlas of the tumor microenvironment, we linked disease-specific signals to the cancer-specific DNA methylation landscape of TAMs. Collectively, these analyses highlighted the role of TGF-beta, IFN-gamma, and CSF1 in the reprogramming of TAMs, mediated by the transcription factors FOSL2, RUNX3, and STAT1. Furthermore, using a reference-free deconvolution approach, we identified a TAM-specific DNA methylation signature associated with high tumor grade and immunosuppressive functions, such as the induction of Cd274, encoding for the immune inhibitory receptor-ligand PD-L1.

Together, these results provide evidence that the epigenetic landscape of macrophages and monocytes is perturbed by breast cancer, reflecting molecular mechanisms of TAM reprogramming and patient outcomes.

In summary, the epigenetic characterization of macrophages from different chronic diseases provides novel insights into the role of DNA methylation and chromatin accessibility in macrophage activation and reprogramming by an altered microenvironment. The results depict that the presence of a muco-obstructive airway or tumor microenvironment has a substantial impact on the epigenome of the respective tissue-resident macrophages and further affects their transcriptional landscapes as well as essential macrophage functions. Furthermore, the data allow the identification of prognostic and diagnostic markers and pave the development of macrophage-targeted therapies.

Document type: Dissertation
Supervisor: Plass, Prof. Dr. Christoph
Place of Publication: Heidelberg
Date of thesis defense: 21 October 2021
Date Deposited: 17 Nov 2021 10:15
Date: 2022
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
DDC-classification: 570 Life sciences
Controlled Keywords: Makrophage, Epigenetik, Brustkrebs, Obstruktive Ventilationsstörung, Mukoviszidose
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