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Cells in the eye of the cytokine storm
The cytokine storm refers to when circulating concentrations of proinflammatory cytokines, such as IL-1β, are greatly increased. The occurrence of cytokine storm syndrome in COVID-19 patients is associated with increased mortality and morbidity. Kothari et al. identified the subtypes and markers of human immune cells that showed the greatest response to IL-1β as assessed primarily by the phosphorylation of the proinflammatory transcription factor NF-κB. These responses were attenuated by anakinra, an antagonist for an IL-1β receptor that is being clinically evaluated to treat cytokine storm syndrome in COVID-19 patients. These data may enable the identification of patients most likely to be afflicted by cytokine storm during COVID-19 infection and other systemic inflammatory syndromes.
Abstract
IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4−CD8low/−CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16−CD56brightCD161− and CD16−CD56dimCD161+), and lineage− (Lin−) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1β–induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1β in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β–neutralizing therapies.
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