The RIPK3-IL-6 axis mediates kidney injury in cytokine storm syndrome

Background : Receptor-interacting protein kinase 3 (RIPK3) is best known as a mediator of necroptosis, a regulated necrosis pathway observed in diseases with high inflammatory components. Methods: We explored the role of RIPK3 in cytokine storm syndrome (CSS)-induced acute kidney injury induced by lipopolysaccharide (LPS) in wild-type and Ripk3- deficient mice. For the in vitro experiments, we treated with LPS both primary tubular epithelial cells and bone marrow-derived cells from wild-type and Ripk3 -deficient mice. Results: Ripk3 deficiency improved renal function and increased survival in CSS, a common condition observed in severe infections and other scenarios, and protection was associated with reduced inflammation. Mechanistically, the necroptosis pathway did not play a key role in kidney protection by Ripk3 deficiency, and the NLRP3 inflammasome was partially implicated. Olink plasma proteomics identified IL-6 as the most upregulated inflammatory protein in the kidney and circulation and was most responsive to Ripk3 deficiency. Ripk3 deficient mice had suppressed kidney, liver and lung Il6 expression as well as suppressed kidney activation of STAT3, a transcription factor downstream of IL-6. In bone marrow chimeric mice, RIPK3-expressing bone marrow-derived cells were required to drive IL-6 expression and AKI and kidney Il-6 expression correlated with loss of renal function. In this regard, in vitro experiments have shown that RIPK3 mediates IL-6 expression in bone marrow cells but not in tubular cells. Additionally, targeting the IL-6 receptor improves kidney function and reduces kidney inflammation in CSS-AKI. Kidney transcriptomic data of human AKI associated with COVID-19 CSS were consistent with activation of the RIPK3-IL-6 axis. Conclusions : The RIPK3-IL-6 axis in bone marrow cells mediates systemic inflammation and kidney injury induced by a cytokine storm, independent of the necroptosis and inflammasome pathways. Specific targeting of bone marrow RIPK3 may limit kidney inflammation, without the potential adverse effects of systemic RIPK3 targeting.