Patients with IFN-mediated autoinflammatory diseases, such as CANDLE and SAVI, present with a variety of severe manifestations, including fever and inflammatory organ damage, and have a high mortality rate. Many of these patients fail to respond to IL-1-blocking agents or other approved therapies for autoinflammatory disease. In this episode, Gina A. Montealegre Sanchez, Raphaela Goldbach-Mansky, and colleagues present the results of compassionate use, dose-escalation study of the JAK1/2 inhibitor baricitinib in small cohort of patients with interferonopathies. Baricitinib treatment reduced clinical manifestations and inflammatory biomarkers in most patients with few adverse effects, supporting the use of JAK inhibitors for this subtype of autoinflammatory disease.
There is a strong variation in pulmonary inflammation depending on the time of day. Airway epithelial cells have been shown to mediate rhythmic inflammatory responses, and loss of the central clock component BMAL1 in airway epithelium augments inflammation. It is not clear how BMAL1 regulates lung inflammation; however, REV-ERB transcription factors, have been proposed to regulate immune function downstream of BMAL1. In this episode, David Ray, Marie Pariollaud and colleagues provide evidence that REV-ERBα couples the pulmonary clock to innate immunity. Inflammatory stimuli were shown to promote REV-ERBα degradation, and complete lack of REV-ERBα further enhanced inflammation in the lungs in following inflammatory challenge. Together, these results identify REV-ERBα as a regulator of rhythmic inflammatory responses in the lung and provide rationale for further exploration of REV-ERBα as a target for inflammatory disease.
White matter injury is associated with neurological dysfunction in a variety of conditions, ranging from cerebral palsy to vascular dementia. Oligodendrocyte progenitor cells (OPCs) are able to regenerate themselves and initiate a repair response following injury; however, the release of hyaluronic acid from the ECM following white matter injury impairs OPC maturation and remyelination. In this episode, Stephen Back and colleagues identify a bioactive hyaluronan fragment (bHAf) that selectively blocks OPC differentiation via activation of a noncanonical TLR4/AKT/FoxO3 signaling pathway. These results elucidate a mechanism by which white matter injury prevents repair and suggest that strategies to overcome this block in OPC maturation have potential for promoting regeneration after injury.
Group B streptococcus (GBS) is part of the normal vaginal flora of approximately 25% of healthy women. Unfortunately, GBS is associated with adverse pregnancy outcomes, due to in utero infection, and can cause serious infections in newborns, including pneumonia, sepsis, and meningitis. In this episode, Lakshmi Rajagopal and colleagues demonstrate that GBS promotes shedding of the vaginal epithelium, which in turn increases bacterial dissemination and ascending GBS infection. Importantly, prevention of epithelial exfoliation in murine models reduced ascending GBS infection and improved pregnancy outcomes.
Charles Sawyers of Memorial Sloan Kettering Cancer Center has defined the molecular lesions that cause cancer and used these insights to develop new drugs. Specifically, Sawyers was one of the critical members of the team that brought imatinib and dasatinib to bear on chronic myeloid leukemia (CML). Furthermore, his work has identified second-generation antiandrogen drugs to treat castration-resistant prostate cancer. This interview reveals personal stories of a physician-scientist called “the greatest cancer researcher of our time” by one of his peers.