Guglielmi, J. | Search bioRxiv

bioRxiv2023

New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure.

BackgroundThe main basic aspects of the regulation of thyroid metabolism by iodine are known, but given the complexity of the mechanisms involved, further analyzes in living animals are still required. Here, we provided new insights into iodine physiology but also into the optimization of radiotherapy with iodine, as well as effective countermeasures in the case of an exposure to radioactive iodine. MethodsWe performed Single Photon Emission Computed Tomography (SPECT) coupled to an X-ray scanner to record radiotracers in living mice and rats. Our imaging system was similar to that routinely used in nuclear medicine but was specifically designed for studies with small animals. Different modalities of administration of radioactive iodine or its radioactive analogues combined with a low or high iodine diet have been studied in pregnant, lactating and control animals. To optimize countermeasures against acute or chronic iodine exposure, the protective effects of potassium iodide (KI) administration protocols were analyzed. Perchlorate was administered to study the iodine metabolism in the kidney and stomach. ResultsOur results showed how the various organs capable of iodine uptake adapt to an iodine-deficient diet. Indeed, the uptake capacity of the thyroid gland, but also that of the salivary glands was significantly increased on a low iodine diet. In contrast, the iodine uptake capacity of the thyroid and lactating mammary glands was reduced on an iodide-rich diet. Our results also showed the physiological role of the kidneys in controlling excess circulating iodide. In addition, they revealed an active iodine cycle in the stomach. We also investigated the protective effects of daily KI administration during radioactive iodine exposure and found that the overall protection was better in rats (85%) than in mice (65%). We also included pregnant females and newborns, and we revealed the existence of specific mechanisms for the inhibition of the fetal thyroid by circulating iodine. Indeed, an iodine-rich diet or repeated daily administration of KI led to a strong inhibition of the iodide uptake capacity of the fetal thyroid. ConclusionsOur study contributes to a better understanding of iodine metabolism and its regulation in the thyroid and in non-thyroidal organs in adult, fetal and newborn animals. Extrapolated to humans, our results not only provide better understanding of iodide withdrawal as a clinical preparatory measure for patients with differentiated thyroid cancer, but also help to optimize countermeasures in the case of an exposure to radioactive iodine.

physiology↗

bioRxiv2021

A ganglioside-based senescence-associated immune checkpoint

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

immunology↗