Long-term obeticholic acid for primary biliary cholangitis in a clinical trial improved event-free survival (death, liver transplantation, and hepatic decompensation) compared with external controls from the GLOBAL PBC real-world database

Mice lacking expression of the phosphatases Sts-1 and Sts-2 (Sts−/−) are significantly resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. Resistance is associated with diminished levels of many inflammatory molecules, a reduction in kidney leukocyte infiltrates by 48 hours post infection, and an absence of inflammatory lesions. Unlike wild type mice, Sts−/− mice clear the infection from the kidney following inoculation with supra-lethal doses. To better understand parameters underlying the Sts−/− phenotype of enhanced resistance, we examined the kinetics of fungal clearance at early time points. We observed enhanced fungal clearance within Sts−/− kidneys beginning at 12–18 hrs. post infection. This corresponds to the timeframe when innate leukocytes such as Ccr2+ inflammatory monocytes (IMs) begin entering the tissue to counter the infection. To examine the role of IMs in promoting enhanced fungal clearance evident in Sts−/− animals, we infected mice lacking Ccr2 expression. Loss of Ccr2 abrogated both the fungal clearance and the survival advantage of Sts−/− mice. Analysis of innate anti-fungal effector responses revealed enhanced production of reactive oxygen species by phagocytes lacking Sts expression, with no apparent differences in the responses of other effector pathways. Downstream of fungal receptor Dectin-1, the Syk kinase was hyper-activated in Sts−/− cells. Our results identify Syk as a target of Sts activity in phagocytes and highlight a novel mechanism regulating the anti-fungal immune response. Further understanding of this regulatory pathway could aid in the development of therapeutics to protect against invasive candidiasis.