Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms.

The tumor microenvironment (TME) considerably influences colorectal cancer (CRC) progression, therapeutic response and clinical outcome, but studies of interindividual heterogeneities of the TME in CRC are lacking. Here, by integrating human colorectal single-cell transcriptomic data from approximately 200 donors, we comprehensively characterized transcriptional remodeling in the TME compared to noncancer tissues and identified a rare tumor-specific subset of endothelial cells with T cell recruitment potential. The large sample size enabled us to stratify patients based on their TME heterogeneity, revealing divergent TME subtypes in which cancer cells exploit different immune evasion mechanisms. Additionally, by associating single-cell transcriptional profiling with risk genes identified by genome-wide association studies, we determined that stromal cells are major effector cell types in CRC genetic susceptibility. In summary, our results provide valuable insights into CRC pathogenesis and might help with the development of personalized immune therapies.