Charting Cell Type-Specific Nucleic Acid Immunity

Introduction

Metabolic and immune pathways form an intricate network that maintains homeostasis. We recently unveiled that the Stimulator of Interferon Genes (STING), central to triggering cytosolic dsDNA-dependent type I Interferon (IFN) responses, inhibits the desaturation of essential dietary polyunsaturated fatty acids (PUFAs).

STING and PUFA Metabolism

STING thereby controls the generation of long-chain PUFAs (LC-PUFAs) that in turn inhibit STING activation. This double negative regulatory feedback loop operates as a key rheostat of homeostasis.

Adipose Tissue and STING

Interestingly, we found that metabolic tissues, such as adipose tissues, express low levels of STING. In vitro adipocyte differentiation leads to STING downregulation, although they retain their ability to produce type I IFNs in response to nucleic acid challenge.

Implications of STING Downregulation

This suggests that alleviating the STING-dependent inhibition of PUFA metabolism may result from, or be required for, adipocyte differentiation or functionality. Further, this also suggests that adipocytes may possess specific STING-independent cytosolic nucleic acid detection pathways.

Research Objectives

Thus, nucleic acid detection pathways and PUFA metabolism should be interrogated concertedly, at the cellular levels, within metabolic tissues, to uncover how they define tissue-specific immune responses and regulate tissue homeostasis, particularly in pathologies presenting with chronic STING activation.

Methodology

Within SENTINEL, we will combine state-of-the-art biochemistry and molecular biology approaches, and cutting-edge omics tools, in vitro and in vivo to identify nucleic acid detection machineries and question the role of STING downregulation in metabolic cells.

Future Directions

Finally, we will explore the impact of STING-dependent metabolic alterations in pathologies presenting with chronic STING activation. SENTINEL will thus chart an unexplored area of nucleic acid immunity (metabolic cell immunity) and reveal its impact on homeostasis and pathologies.