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

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. 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 both primary tubular epithelial cells and bone marrow-derived cells from wild-type and Ripk3-deficient mice with LPS. 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 it was most responsive to Ripk3 deficiency. Ripk3-deficient mice had suppressed kidney, liver, and lung Il-6 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. 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.