Charting Cell Type-Specific Nucleic Acid Immunity

Project Information

SENTINEL

Grant agreement ID: 101087092

DOI

10.3030/101087092

EC signature date 7 April 2023

Start date 1 October 2023

End date 30 September 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 1 - SENTINEL (Charting Cell Type-Specific Nucleic Acid Immunity)

Reporting period: 2023-10-01 to 2026-03-31

Summary of the context and overall objectives of the project

Metabolic and immune pathways are tightly interconnected, working together to maintain tissue and organismal homeostasis. Our recent work revealed an unexpected link between the innate immune sensor STING (Stimulator of Interferon Genes) and lipid metabolism. STING, best known for triggering cytosolic DNA-dependent type I interferon responses, also inhibits the desaturation of essential dietary polyunsaturated fatty acids (PUFAs). This establishes a double negative feedback loop: while STING suppresses the generation of long-chain PUFAs (LC-PUFAs), these LC-PUFAs, in turn, inhibit STING activation. This feedback system functions as a molecular rheostat, fine-tuning immune and metabolic balance.

Our preliminary findings suggest that this regulatory network operates in a tissue-specific manner. For instance, metabolic tissues such as adipose tissue express very low levels of STING, and STING expression decreases further during adipocyte differentiation. Yet, adipocytes remain fully competent to produce type I interferons upon nucleic acid challenge. These results point to two intriguing possibilities: (i) the release of STING-mediated inhibition of PUFA metabolism may be necessary for adipocyte differentiation and function, and (ii) adipocytes may rely on distinct, STING-independent pathways for cytosolic nucleic acid detection.
Based on these observations, our project SENTINEL aims to investigate the interplay between nucleic acid detection pathways and PUFA metabolism within metabolic tissues. We will use cutting-edge molecular, biochemical, and omics-based approaches, both in vitro and in vivo, to identify the specific nucleic acid sensing machineries active in adipocytes and to determine how STING downregulation contributes to metabolic cell function.

By uncovering how immune surveillance and lipid metabolism are co-regulated in metabolic tissues, SENTINEL will open a new field of investigation at the intersection of metabolism and innate immunity. This work is expected to:
• Reveal tissue-specific mechanisms of immune regulation, with a particular focus on metabolic cells.
• Clarify the role of STING downregulation in metabolic cell differentiation and function.
• Provide novel insights into pathologies characterized by chronic STING activation, including inflammatory and metabolic disorders.

Ultimately, SENTINEL will shed light on a previously unexplored dimension of nucleic acid immunity (ie: metabolic cell immunity) and establish its significance for tissue homeostasis and disease. The project is thus expected to generate fundamental knowledge with potential long-term implications for developing new therapeutic strategies targeting metabolic and inflammatory diseases.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The completion of the SENTINEL project relies on the establishment of tools and models allowing the examination of the communication between STING-dependent nucleic acid immunity and metabolism, but also uncovering alternative STING-independent pathways that can take in charge the production of type I Interferons and the subsequent responses under threat.

Since the beginning of the project, we have developed methodologies and tools necessary to investigate the interplay between innate immune responses and metabolic homeostasis, including implementing complex diseases models. Our main achievements so far are:

- Performing and analyzing spatial transcriptomics datasets obtained from our in vivo models of inflammation. This allows us to delve into the complexity and cell type heterogeneity of the metabolic and transcriptomics responses at the tissue level
- The identification of novel pathways involved in the detection of pathological nucleic acid species. Using a combination of quantitative proteomics, transcriptomics and kinome analyses, we identify a novel pathway involved in the regulation of nucleic acid associated inflammatory responses.
- The identification of novel nuclear proteins that regulate nucleic acid immunity. We show that chromatin bound proteins may be mobilized to the cytosol to ensure nucleic acid detection, and that as a side effect a de-repression of endogenous retroelements ensues, leading to a feed forward loop of inflammatory responses
- We identify a DNA damage response protein involved in the termination of STING-associated signaling, opening new perspectives in the manipulation of this pathway and opening the way to better understanding of the interplay between DNA damage responses and inflammatory signaling.
- The establishment of original mouse models to study the impact of lipid metabolism on chronic inflammatory pathologies

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The work we are currently performing opens novel perspectives in the understanding of the tight interconnexion between innate immune pathways and metabolic responses in health and disease. Some of the targets we identify will necessitate further spin-off work in order to explore their full valorization and treatment potential. Support from our host institute, notably enabling the stabilization of the research staff, but also for IPR applications, and applications to tech transfer grants will help us bring our innovations to the market in the future and/or have a biomedical impact.