Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury.

Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19-affected lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.

Bile acid receptor agonists in primary biliary cholangitis: Regulation of the cholangiocyte secretome and downstream T cell differentiation.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non-responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4+ T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co-cultured with CD4+ T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 (P = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL-6 release (P = 0.044). Bile acid receptor expression was assessed in PBC patients with well-characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL-6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation.

Novel bile acid therapeutics for the treatment of chronic liver diseases.

Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases.