Search

Excessive levels of circulating proinflammatory mediators, known as "hypercytokinemia," that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens. STING activation, particularly within cells of the innate immune system, triggers potent type I interferon and proinflammatory cytokine production. We thus hypothesized that generalized expression of a constitutively active STING mutant in mice would lead to hypercytokinemia. To test this, a Cre-loxP-based system was used to cause the inducible expression of a constitutively active hSTING mutant (hSTING-N154S) in any tissue or cell type. Herein, we employed a tamoxifen-inducible ubiquitin C-CreERT2 transgenic to obtain generalized expression of the hSTING-N154S protein, thereby triggering the production of IFN-β and multiple proinflammatory cytokines. This required euthanizing the mice within 3 to 4 d after tamoxifen administration. This preclinical model will allow for the rapid identification of compounds aimed at either preventing or ameliorating the lethal effects of hypercytokinemia., Competing Interests: Conflict of interest: The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

DNA repair proteins are critical to the maintenance of genomic integrity. Specific types of genotoxic factors, including reactive oxygen species generated during normal cellular metabolism or as a result of exposure to exogenous oxidative agents, frequently leads to "ragged" single-strand DNA breaks. The latter exhibits abnormal free DNA ends containing either a 5'-hydroxyl or 3'-phosphate requiring correction by the dual function enzyme, polynucleotide kinase phosphatase (PNKP), before DNA polymerase and ligation reactions can occur to seal the break. Pnkp gene deletion during early murine development leads to lethality; in contrast, the role of PNKP in adult mice is unknown. To investigate the latter, we used an inducible conditional mutagenesis approach to cause global disruption of the Pnkp gene in adult mice. This resulted in a premature aging-like phenotype, characterized by impaired growth of hair follicles, seminiferous tubules, and neural progenitor cell populations. These results point to an important role for PNKP in maintaining the normal growth and survival of these murine progenitor populations., (© 2021 Shin et al.)