In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The JCI accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Psoriasis is a chronic inflammatory disease that is characterized by the presence of pruritic skin lesions. Aberrant interactions between the epithelia and immune system underlie the disease; however, the pathways that promote psoriasis are poorly understood. In this episode, Peter Marinkovich and Mårten Winge discuss their work, which shows that hyperactivation of RAC1 in the skin drives pathogenic interactions between the epidermis and the immune system in psoriasis. The results of this work suggest that RAC1 is a potential therapeutic target for this disease.
The skin serves as a powerful barrier against microbial, physical, and chemical insults and is maintained through constant proliferation and differentiation of epidermal cells. However, the mechanisms that regulate skin homeostasis are not fully understood. In this episode, Hisahiro Yoshida describes the development and characterization of a strain of mice that exhibit progressive pruritic dermatitis due to the presence of a mutation that results in hyperactivation of JAK1 tyrosine kinase. Treatment of these mice with JAK1 inhibitors delayed disease onset, indicating that JAK1-mediated signaling plays an important role in maintenance of skin barrier function.
Sex-specific differences have been observed in preclinical models of renal ischemic injury. In particular, females recover more readily from ischemia-reperfusion injury (IRI) than males, and testosterone has been shown to have a negative effect on renal ischemia tolerance. The factors that underlie these sex-dependent discrepancies are poorly understood, and it is not clear if these same differences extend to humans. In this episode, Matthew Levine and David Aufhauser describe the development of several murine renal ischemia and transplant models used to evaluate sex-specific effects on recovery after IRI. Their results demonstrate that recipient, not donor, sex determines transplantation outcomes. Moreover, evaluation of patient data from the United Network for Organ Sharing revealed that male recipients had increased delayed graft function compared to female recipients.
The specialized endothelial cells of the blood-brain barrier (BBB) protect the brain from toxic substances, while allowing oxygen and other nutrients to pass through. The selectivity of the BBB also prevents delivery of therapeutic agents to the brain that could benefit patients with neurological diseases. In this episode, Margaret Bynoe reveals that activation of the A2A adenosine receptor (A2A AR) with the FDA-approved agonist Lexiscan reversibly reduced expression of the drug efflux transporters P-glycoprotein and BCRP1. Moreover, in mouse models, Lexisacn treatment resulted in a greater accumulation of chemotherapeutic drugs in the brain. The results of this study indicate that targeting A2A AR should be further explored for improving drug-delivery to the brain.
Nonalcoholic steatohepatitis (NASH) is the most common liver disease in the US and can lead to cirrhosis, cancer, and death; however, the drivers of NASH development are poorly understood. In this episode, Wajahat Mehal and colleagues reveal that levels of mitochondrial DNA, which activates TLR9, are elevated in plasma of mice and patients with NASH. Importantly, pharmacological or genetic inhibition of TLR9 blocked NASH development in mice fed a high-fat diet. The results of this study identify TLR9 activation via mitochondrial DNA as a driver of NASH and suggest targeting this pathway should be further explored for treatment of NASH.