STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses.

Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes.

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

Impact of Cancer-Associated Fibroblast on the Radiation-Response of Solid Xenograft Tumors.

Increasing evidence indicates that the heterogeneous tumor stroma supports therapy resistance at multiple levels. Fibroblasts, particularly cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma. However, the impact of CAFs on the outcome of radiotherapy (RT) is poorly understood. Here, we investigated if and how fibroblasts/CAFs modulate the radiation response of malignant tumors by altering cancer cell radiosensitivity or radioresistance in vitro and in vivo. The influence of fibroblasts on cancer cell proliferation, cell death induction and long-term survival after RT was studied using different sets of fibroblasts and cancer cells in an indirect co-culture (2D) system to analyse potential paracrine interactions or a 3D model to study direct interactions. Paracrine signals from embryonic NIH-3T3 fibroblasts promoted MPR31.4 prostate and Py8119 breast cancer cell proliferation. Indirect co-culture with L929 skin fibroblasts induced higher levels of apoptosis in irradiated MPR31.4 cells, while they promoted proliferation of irradiated Py8119 cells. In addition, NIH-3T3 fibroblasts promoted long-term clonogenic survival of both tumor cell types upon irradiation in the 3D co-culture system when compared to non-irradiated controls. Also in vivo, co-implantation of cancer cells and fibroblasts resulted in different effects depending on the respective cell combinations used: co-implantation of MPR31.4 cells with NIH-3T3 fibroblasts or of Py8119 cells with L929 fibroblasts led to increased tumor growth and reduced radiation-induced tumor growth delay when compared to the respective tumors without co-implanted fibroblasts. Taken together, the impact of fibroblasts on cancer cell behavior and radiation sensitivity largely depended on the respective cell types used as they either exerted a pro-tumorigenic and radioresistance-promoting effect, an anti-tumorigenic effect, or no effect. We conclude that the plasticity of fibroblasts allows for such a broad spectrum of activities by the same fibroblast and that this plasticity is at least in part mediated by cancer cell-induced fibroblast activation toward CAFs.