Kim CG, et al. Immune Netw. 2023 Dec;23(6):e47. https://doi.org/10.4110/in.2023.23.e47

Current studies have elucidated the mechanisms of radiation-induced skin injury (RISI) and identified several medical countermeasures to reduce its severity. However, no treatment has yet proven effective in preventing or reversing radiation-induced skin fibrosis. Here, we show that radiation upregulates lipoprotein-associated phospholipase A2 (Lp-PLA₂) expression and induces endothelial cell dysfunction, characterized by an increased DNA damage response and reduced tube-forming capacity and mitochondrial function. To define the role of Lp-PLA₂ in the progression of RISI, we treated human dermal microvascular endothelial cells and the skin of SKH1 hairless mice with darapladib, a selective Lp-PLA₂ inhibitor. In endothelial cells, darapladib attenuated radiation-induced cellular damage and suppressed endothelial-to-mesenchymal transition (EndoMT). In irradiated mouse skin, darapladib reduced radiation-induced inflammation, adipose tissue disruption, dermal thickness, and skin fibrosis. Notably, darapladib modulated macrophage polarization and inhibited radiation-induced macrophage infiltration in irradiated skin. These findings suggest that Lp-PLA₂ inhibition may reveal potential targets for the treatment of RISI and other fibrotic skin diseases.

Dietary restrictions are increasingly recognized as modulators of immune cell function. However, how they shape CD8 ⁺ T cell fate decisions remains incompletely understood. Here, we investigated the impact of intermittent fasting (IF) on differentiation of heterogeneous effector T cell subsets and the formation of a long-lived homeostatic memory pool. We found that IF skewed CD8 ⁺ T cell differentiation toward memory precursor effector cells (MPECs) and enhanced the central memory CD8 ⁺ T cell development and functions. Mechanistically, glucose restriction induced by IF promotes alternative metabolic fluxes leading to fatty acid oxidation. This metabolic shift enhanced mitochondrial fitness and supported MPEC differentiation via metabolic-epigenetic cross-talk, culminating in durable and functionally robust memory CD8 ⁺ T cell responses. Applying this strategy in adoptive transfer therapy, intratumoral defects could be circumvented by imprinting a memory phenotype under IF-mimicking conditions, resulting in improved and long-lasting antitumor activity. Collectively, these findings underscore the importance of IF in orchestrating metabolic-epigenetic cross-talk to enhance memory formation and antitumor immunity.