Necroptosis drives cytokine release syndrome in response to Francisella tularensis infection 3946

Abstract Description The pathogenesis of a number of human pathogens, including SARS-CoV2, Ebolavirus and Francisella tularensis, is due to the uncontrolled elicitation of a systemic inflammatory response, termed the cytokine storm, resulting in cytokine release syndrome (CRS) and leading to systemic inflammatory disease syndrome (SIDS). The cytokine storm represents the dysregulated production of a yet undefined makeup of pro-inflammatory and regulatory cytokines. In addition, the molecular trigger for the dysregulation of the cytokine storm is not defined. In this study, F. tularensis was used to trigger the cytokine storm to uncover the source of this dysregulation. This study revealed a sexual dimorphism in the inflammatory response controlled by the regulation of RIPK1 between necroptosis and ripoptosis in macrophage subsets. Molecular analysis revealed an enhanced usage of necroptotic pathway effector molecules in samples with increased inflammatory responses. Chemical inhibition of the necroptosis effector protein MLKL abolished the disparity normalizing the inflammatory response while genetic depletion of MLKL completely abolished cytokine production. This study demonstrates that cytokine production in CRS and SIDS following infectious stimuli is dependent on the elicitation of the cell death pathway necroptosis. Funding Sources NIH SC1AI148753 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)