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Deciphering the dialogue between intestinal macrophages and their tissular niches

Project description

The role of macrophages in tissue homeostasis

Macrophages are key immune cells with a scavenging role in different tissues. Emerging evidence indicates that impaired macrophage function in the gut leads to chronic inflammation. The EU-funded DIALOG project is interested to understand the crosstalk between macrophages and their resident tissues and how it dictates macrophage identity. Researchers will characterise the profile of macrophages in different locations in the gut and study the functional outcome of experimentally depleting macrophages. DIALOG will generate important insight into the role of macrophages in maintaining homeostasis in the intestinal niche, which may be shared by other tissues.

Objective

Besides their role as immune sentinels, macrophages fulfil specific functions that are strictly related to their tissue of residence. As an example, the loss of gut macrophages is correlated with impaired crypt cells differentiation which might favour the establishment of chronic intestinal inflammation. Macrophage functions are known to be regulated by tissular niches that imprint the macrophage tissue-specific identity. However, little is known about the “feedback” role of the macrophage for the maintenance and function of its niche. I hypothesise that the loss of a given macrophage subset might imperil its microenvironment through the alteration of its niche cells function or maintenance. Unravelling this feedback mechanism is technically challenging. Current mouse models target macrophages themselves, inducing their rapid replacement by circulating monocytes and thus preventing their long term depletion. Here, I will take advantage of their dependence to a continuous provision of trophic factors by their niche to manipulate and study gut macrophages in a novel manner. First, I will unravel the composition of each gut macrophage niches in a global and unbiased approach by combining single cells and spatial transcriptomics. Next, I will determine the potential cellular sources of trophic factors in each gut niches. Once identified, I will use specific mouse models to delete the trophic factor in the candidate cells to induce a long term depletion of a given macrophage subset. Finally, I will unravel the function of macrophages to their niche by analysing in silico the niche cells transcriptome after macrophage loss to highlight potential molecular interactions between the macrophage and the niche that would induce the survival or differentiation of niche cells. They would eventually be confirmed in vivo by using specific mouse models.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

(opens in new window) H2020-MSCA-IF-2020

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Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution
€ 184 707,84
Address
RUE DE TOLBIAC 101
75654 Paris
France
Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Total cost
€ 184 707,84

Participants (1)