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.
