Innate lymphoid cells and tissue adaptation to changing metabolic needs

Informacje na temat projektu

ILCADAPT

Identyfikator umowy o grant: 101055309

DOI

10.3030/101055309

Data podpisania przez KE 3 Czerwca 2022

Data rozpoczęcia 1 Listopada 2022

Data zakończenia 31 Października 2027

Finansowanie w ramach

• European Research Council (ERC)

Koszt całkowity

€ 2 379 266,00

Wkład UE

€ 2 379 266,00

Koordynowany przez

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Periodic Reporting for period 1 - ILCADAPT (Innate lymphoid cells and tissue adaptation to changing metabolic needs)

Okres sprawozdawczy: 2022-11-01 do 2025-04-30

Podsumowanie kontekstu i ogólnych celów projektu

The surfaces of our body that come into contact with the outside world—like the skin, lungs, and especially the gut—are in constant communication with the environment. These border areas are buzzing with activity, as networks of cells (including epithelial, stromal, and immune cells) work together to process and respond to environmental signals. This ongoing interaction helps our bodies adapt and stay healthy.

Although we are only beginning to understand the molecular details behind these important processes, they play a crucial role in keeping our organs functioning properly and our protective barriers intact. When this delicate system of adaptation breaks down—a condition known as maladaptation—it can set the stage for chronic diseases, particularly those with an inflammatory component, like obesity and type 2 diabetes.

This proposal seeks to uncover the molecular networks that support healthy adaptation, focusing on how specific immune cells known as group 3 innate lymphoid cells (ILC3) interact with cells in the gut lining. By exploring how these cells work together to manage changes in our body’s metabolic needs, we hope to pinpoint new biological pathways that could be targeted to prevent or treat metabolic and inflammatory diseases. Given the rising rates of these conditions, this research is not only scientifically exciting but also an urgent healthcare and societal priority.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

We have made significant progress on several aspects of the ILCADAPT proposal.

1. A New Tool for Studying the Immune System
We've developed a new mouse model that lets us study a specific group of immune cells called ILC2s more precisely than ever before. This model helps us understand the unique role ILC2s play in certain immune responses, without interfering with other parts of the immune system. This is a big step forward for scientists working in this field.

2. Understanding How the Environment Affects Our Immune System
We have discovered that the immune system plays an important role in how living organisms adapt to changes in their environment. To study this in more detail, we have built experimental setups that let us control environmental factors more closely—including the microorganisms that live in and on us (our microbiota). One of our major achievements here was setting up a special research unit where we study mice with microbiota similar to those of wild mice. This approach better mimics real-world biology and has already led to two published studies (below).

3. New Insights into Immune Cell Communication
We found a new way that two types of immune cells—ILC1s and macrophages—talk to each other. When a specific receptor (called NKp46) on ILC1s is activated, it leads these cells to produce a signaling molecule that helps grow and shape a population of macrophages. We found this interaction plays a key role in a disease called lupus nephritis, and blocking the receptor prevented the disease in mice. This finding challenges the idea that autoantibodies alone cause autoimmune damage—showing that this immune cell interaction is also necessary.

Publications

Jarick KJ, Topczewska PM, Jakob MO, Yano H, Arifuzzaman M, Gao X, Boulekou S, Stokic-Trtica V, Leclère PS, Preußer A, Rompe ZA, Stamm A, Tsou AM, Chu C, Heinrich FR, Guerra GM, Durek P, Ivanov A, Beule D, Helfrich S, Duerr CU, Kühl AA, Stehle C, Romagnani C, Mashreghi MF, Diefenbach A, Artis D, Klose CSN. Non-redundant functions of group 2 innate lymphoid cells. Nature. 2022; 611:794-800. doi: 10.1038/s41586-022-05395-5. PMID: 36323785; PMCID: PMC7614745.

Drude N, Nagel-Riedasch S, Rosshart SP*, Diefenbach A*; “Charité 3R Wildling Mouse Model in Health and Disease (C3R Wildling HeaD)” consortium; Jordan S*. A facility for laboratory mice with a natural microbiome at Charité - Universitätsmedizin Berlin. Lab Anim (NY). 2024; 53:351-354. doi: 10.1038/s41684-024-01474-4. PMID: 39533119; PMCID: PMC11599040. *equally contributing senior and corresponding authors.

Drude N, Diederich K, Duerr CU, Haase N, Harms C, Heppner F, Jendrach M, Kahnau P, Kolesnichenko M, Lewejohann L, Kurreck C, Lohan A, Mall MA, Müller D, Nagel-Riedasch S, Opitz B, Schaupp L, Schönfelder G, Weber A, Willimsky G, Zang Y, Rosshart SP*, Diefenbach A*, Jordan S*. Operating and Biocontainment Procedures of a Facility for Laboratory Mice with a Natural Microbiome: Immunophenotyping Procedure. J Vis Exp. 2024. doi: 10.3791/67100. PMID: 39760355. *equally contributing senior and corresponding authors.

Biniaris-Georgallis SI, Aschman T, Stergioula K, Schreiber F, Jafari V, Taranko A, Karmalkar T, Kasapi A, Lenac Rovis T, Jelencic V, Bejarano DA, Fabry L, Papacharalampous M, Mattiola I, Molgora M, Hou J, Hublitz KW, Heinrich F, Guerra GM, Durek P, Patone G, Lindberg EL, Maatz H, Hölsken O, Krönke G, Mortha A, Voll RE, Clarke AJ, Hauser AE, Colonna M, Thurley K, Schlitzer A, Schneider C, Stamatiades EG, Mashreghi MF, Jonjic S, Hübner N, Diefenbach A*, Kanda M*, Triantafyllopoulou A*. Amplification of autoimmune organ damage by NKp46-activated ILC1s. Nature. 2024; 634:952-960. doi: 10.1038/s41586-024-07907-x. PMID: 39137897. *equally contributing senior and corresponding authors.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

Our discovery that ILC1 cells regulate both the growth and development of macrophages is a major breakthrough. Not only does this provide strong evidence for a coordinated ILC-macrophage partnership, but it also challenges a long-standing belief in autoimmune research: that simply having autoantibodies—those immune molecules that mistakenly target the body’s own tissues—is enough to cause organ damage.

What we found tells a different story. Autoimmune tissue damage doesn’t happen in isolation. It requires additional players from the innate immune system. This insight opens the door to a whole new set of therapeutic targets for treating autoimmune diseases—ones that go beyond just managing autoantibodies.

These findings were unexpected, especially since autoimmune research has traditionally focused almost entirely on the adaptive immune system. Our work adds an important piece to the puzzle, shifting the spotlight toward innate immune interactions and revealing promising new avenues for intervention.

Publication:
Biniaris-Georgallis SI, Aschman T, Stergioula K, Schreiber F, Jafari V, Taranko A, Karmalkar T, Kasapi A, Lenac Rovis T, Jelencic V, Bejarano DA, Fabry L, Papacharalampous M, Mattiola I, Molgora M, Hou J, Hublitz KW, Heinrich F, Guerra GM, Durek P, Patone G, Lindberg EL, Maatz H, Hölsken O, Krönke G, Mortha A, Voll RE, Clarke AJ, Hauser AE, Colonna M, Thurley K, Schlitzer A, Schneider C, Stamatiades EG, Mashreghi MF, Jonjic S, Hübner N, Diefenbach A*, Kanda M*, Triantafyllopoulou A*. Amplification of autoimmune organ damage by NKp46-activated ILC1s. Nature. 2024. 634(8035):952-960. doi: 10.1038/s41586-024-07907-x. PMID: 39137897. *equal contribution, corresponding/senior authors