Blanc SVSE 3 - Blanc - SVSE 3 - Microbiologie, immunologie, infectiologie

Pro-inflammatory immunity and intestinal homeostasis – INFHOM

The role of pro-inflammatory immunity in maintaining intestinal equilibrium

Understanding inflammation, the strong arm of the immune system required to control the immense microbial flora that resides in our intestine. Understanding how rupture of the equilibrium leads to intestinal inflammatory disease.

Towards new preventive and therapeutic strategies against inflammatory diseases of the intestine

Inflammatory bowel disease, including Crohn's disease and colitis, affect more than 1% of the western population. Current treatments include partial immunosuppression, antibiotics and surgery. We aim at understanding how rupture of the intestinal equilibrium leads to inflammatory disease, and at developing new and more specific preventive and therapeutic strategies against such diseases.

Mice are the choice model to study inflammatory diseases of the intestine. We have developped mice models that allow to visualize the RORgt+ pro-inflammatory cells, as well as to isolate and ablate them. We are now measuring the impact of RORgt+ cells on the progression of the inflammatory disease.

We have found that a communication network is established between the symbiotic bacteria of the gut, epithelial cells, dendritic cells and the pro-inflammatory RORgt+ cells. We aim now at understanding the language of this network in order to control it.

Our work will allow to control the pro-inflammatory cells of the intestine during the inflammatory disease, or to control these cells in order to prevent development of the inflammatory disease. Inhibitors of RORgt are already being developed at major pharmaceutical companies.

To come

It was discovered in 2003 that IL-23, rather than IL-12, is driving autoimmune inflammation in a number of disease models, such experimental autoimmune encephalomyelitis. Two years later, it was shown that IL-23 promotes the generation of pathogenic IL-17-producing T cells, termed Th17 cells. A growing literature now shows that the natural function of Th17 cells, rather than inducing autoimmunity, is mucosal defense against bacterial, fungal and viral infections. Th17 cells are enriched in the intestine where they are efficiently induced by bacterial symbionts, such as segmented filamentous bacteria (SFB), in the absence of apparent infection and inflammatory disease. We have therefore suggested that Th17 cells, which also produce IL-22 critically involved in epithelial defense, are necessary to maintain intestinal homeostasis with the large symbiotic microbiota. In agreement with this view, our recent data show that mice deficient in type 17 immunity are highly susceptible to colitis as a consequence of decreased microbial containment. In addition, we found that a subset of innate lymphoid cells (ILCs) constitutively expresses IL-17, as well as most of intestinal IL-22. The development and activity of ILCs pre-empt the bacterial colonization of the intestine, and expand in the context of infection and colitis. This project aims at understanding how the symbiotic microbiota induces and regulates type 17 immunity mediated by Th17 cells and ILCs, and how these cells control the microbiota during homeostasis. The project next aims at understanding how this homeostatic crosstalk breaks down during inflammatory pathology, and at defining pathways to re-establish homeostasis and health.

Project coordinator

Monsieur Gérard EBERL (INSTITUT PASTEUR) – gerard.eberl@pasteur.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP INSTITUT PASTEUR

Help of the ANR 600,000 euros
Beginning and duration of the scientific project: December 2011 - 48 Months

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