Identification of human immune cell subtypes most responsive to IL-1β–induced inflammatory signaling using mass cytometry

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.

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

“…The results suggested that IL‐2 receptor activation might be involved in epileptogenesis through SOCS1/STAT5 signaling pathway. In addition, STAT5 was also regulated by IL‐1β and IL‐6 33 . As different expressions of pro‐inflammatory factors and stat5 expressions were found in the three transgenic zebrafish lines, we inferred that STAT5 signaling might be one of the important pathways responsible for epileptogenesis and be related to the severity of seizure onset.…”

Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators

“…Interferon-γ causes fever, headache, dizziness, chills, and fatigue symptoms associated with CS. Elevated Interleukin-1 levels that act via nuclear factor κB (NF-κB) pathway can be modulated by interleukin-1–receptor antagonist anakinra to overcome cytokine storm [267] .IL-6 is a pleotropic cytokine, activates two varied pathways the classical and the trans-signaling pathways [268] . Its receptor IL-6R exits in two distinct forms membrane‐bound IL‐6 receptor MIL-6R and soluble sIL-6R which is cleaved by A disintegrin and metalloprotease 17 domain(ADAM17).…”

“…Th2 cells activate basophils, eosinophils, and mast cells via IL4 and IL-6 which essentially coordinate the humoral response [278] . In addition, IL-6 can even induce suppressor of cytokine signaling 3 (SOCS-3) along with an increase in PD-1 expression which are capable of overcoming the cell-induced antiviral response leading to the cytokine storm [276] , [267] . The ratio of partial pressure arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) serves as an indicator of hypoxemia and is reported to be inversely proportional to IL-6 in Covid -19 patients [280] According to a study done by Santa Cruz, A et al, IL-6 levels were negatively correlated to peripheral oxygen saturation (SpO2), and partial pressure of oxygen in arterial blood (PaO2) serves as predictor of respiratory failure and the need for mechanical ventilation of the critically ill patients [281] .…”

Integrated Analysis of microRNAs and Metabolomics in Rat’s Serum Reveals Multi-action Modes of Qingfei Paidu Decoction for COVID-19 Treatment

“…Involving regulation of immunity [114,115], in ammatory cytokines [114,[116][117][118][119][120], pulmonary brosis [121], and virus infection, e.g., SARS-CoV-2, H1N1 [115][116][117][119][120][121][122][123][124] Cytokine-cytokine receptor interaction…”