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Studying in vivo differentiation of monocytes into intestinal macrophages and their impact on gut homeostasis

Final Report Summary - MONOTOMACRO (Studying in vivo differentiation of monocytes into intestinal macrophages and their impact on gut homeostasis)

Mononuclear phagocytes comprise blood monocytes and tissue-resident macrophages and dendritic cells (DC). Given their phagocytic activity, and the potency of DC to induce adaptive immunity, mononuclear phagocytes have been primarily recognized for their role in host defense against infections and removal of apoptotic cells. More recently though, these cells are also appreciated for their critical contributions to organ development, as well as the maintenance of tissue homeostasis, both in steady state and during inflammation. Finally, mononuclear phagocytes also drive tissue pathologies and strategies aiming to manipulate their differentiation, therefore, hold major therapeutic promise.
Our ERC project focused on the differentiation of blood monocytes into a specific population of macrophages that resides in the intestinal connective tissue underlying the gut epithelium. Among tissue macrophages, these cells represent an exception that might be related to the unique homeostatic challenge of this organ by microbiota and other dynamic exogenous stimuli.
At the beginning of ERC funding period, we completed a study that focused on the molecular definition of tissue macrophages, including transcriptomes and epigenomes (Lavin et al. Cell 2014). This study was one of the first to highlight the impact the tissue environment has on macrophage signatures and emphasize macrophage heterogeneity.
In parallel, we performed a molecular characterization of distinct blood monocyte populations and their precursors in the bone marrow, including population and single cell transcriptomics, coupled with epigenetic approaches (Mildner et al, 2017).
A major section of our project was dedicated to the investigation of gut macrophages, their derivation from monocytes and their communication with the gut environment. Here, we used an established experimental paradigm that is based on the conditional ablation of intestinal macrophages and their reconstitution by monocyte grafts (Varol et al 2007, 2009), to study the molecular cues guiding monocyte differentiation into gut macrophages (Gross-Vered et al 2019). Furthermore, we investigated, in extension of an earlier study by Zigmond et al.2014 the cellular players that are critical for the development of gut inflammation driven by IL10R deficient macrophages (Bernshtein et al 2019).
We believe the comparative analysis of tissue macrophages and the definition of their distinct strategies to cope with the tissue context and its peculiar challenges can critically add to our understanding of macrophages. Our laboratory therefore also focuses on the study of macrophages in other tissues, such as the brain and the fat tissue. Moreover, the necessity to study macrophages in their physiological context, motivates us to continuously refine our experimental approaches.
In depth understanding of macrophage ontogeny and their functional contributions to tissue homeostasis and pathology should allow for the future development of rational cell target therapies.