Unveiling metabolic impact on lung cell death - 20/03/24

The lung is a crucial organ that directly interacts with the external environment, stressing the importance of keeping tissues and cells healthy. This highlights the close link between controlling cell death and lung diseases like asthma or pneumonia. As lung diseases are a major cause of death worldwide, there is an urgent for new treatments that include ways to reduce cell death. Hence, expanding on our recent findings related to the host-derived antiviral metabolite succinate (EMBO J., 2022), as well as the antiviral and immunoregulatory metabolite “C2” (named so due to a pending patent application), our present study explores the potential of C2 in modulating cell death mechanisms.

We exposed human bronchial epithelial cell lines as well as primary cells to distinct agonists of cell death pathways, including apoptosis, necroptosis and pyroptosis in the presence or absence of the metabolite C2. We further evaluated cell viability/death by measuring cell metabolic activity, membrane permeabilization and cell morphology using the quantitative and real-time live cell assays technology Incucyte®.

We found that C2 has a potent anti-apoptotic effect, likely through the regulation of “Cellular Inhibitor of Apoptosis 1” (cIAP-1)-dependent mechanism. Moreover, C2 also diminishes cIAP-1-dependent necroptosis. In these two cell death contexts, C2 preserves cell morphology, metabolic activity, and membrane integrity. Additionally, the specificity of C2's impact on the cIAP-1 pathway is supported by its lack of effect on cytochrome C-induced apoptosis. In contrast, C2 exacerbates pyroptosis induced by ATP, an activator of the NLRP3 inflammasome pathway.

This preliminary study uncovers the dual functions of host-derived C2 in regulating cell death. C2 demonstrates both anti-apoptotic and anti-necroptotic properties, while also displaying pro-pyroptotic effects, illustrating its complex role in cell death control. While the precise molecular mechanisms require further investigations, our results suggest promising opportunities for developing C2-based cell death modulators. This could greatly enhance our therapeutic targets against lung diseases.