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MONOTOMACRO Report Summary

Project ID: 340345
Funded under: FP7-IDEAS-ERC
Country: Israel

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

Mononuclear phagocytes (MNP) comprise blood monocytes and tissue-resident macrophages and dendritic cells (DC). Given their phagocytic activity, and the potency of DC to induce adaptive immunity, MNP have been primarily recognized for their role in host defense against infections and removal of apoptotic cells. More recently though, MNP 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, MNP also drive tissue pathologies and strategies aiming to manipulate MNP differentiation therefore hold major therapeutic promise.
Our ERC project focuses 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.
In the past funding period we completed a study that focused on the molecular definition of tissue macrophages (Lavin et al. Cell 2014), including transcriptomes and epigenomes. Our results highlight the impact the tissue environment has on macrophage signatures and emphasize macrophage heterogeneity. More recently, 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. This allowed us to show that the reported homeostatic default differentiation of Ly6C+ monocytes into Ly6C- cells (Varol et al 2007, Yona et al 2013) occurs with minor epigenetic changes in a predetermined enhancer landscape. Generation of Ly6C- monocytes involved a transcription factor isoform shift from C/EBPα to C/EBPß. Moreover, C/EBPß - deficient mice lacked Ly6C- monocytes. Mechanistically, C/EBPß was found to bind to the Nr4a1 promoter and induce expression of this established monocyte survival factor (Mildner et al, in preparation).
The second half of our project is dedicated to the investigation of gut macrophages, their derivation from monocytes and their communication with the gut environment. 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. Here, we identified key transcription factors that guide monocyte differentiation in colon vs. small intestine and are currently in the process to test their in vivo relevance using the respective mutant animals. In a parallel project, we study the impact of pro-inflammatory, IL10 receptor-deficient macrophages (Zigmond et al. 2014) on the gut epithelium, the luminal and mucosa-associated microbiota composition and other innate and adaptive immune cells.
Finally, in our ongoing efforts to reveal tissue macrophage contributions to organismal homeostasis, we discovered a previously unappreciated role of brown adipose tissue macrophages in the control of sympathetic tissue innervation and energy expenditure. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator methyl-CpG binding protein 2 (MeCP2) in defined tissue macrophages. The resulting animals displayed altered body composition and spontaneous obesity, which resulted from impaired brown adipose tissue (BAT) function. Specifically, mutagenesis of a BAT-resident macrophage subpopulation resulted in decreased sympathetic innervation and lower local norepinephrine tigers, resulting in reduced adipocyte expression of the thermogenic factors UCP1 and DIO2. A manuscript summarizing these findings is currently under review.

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