Bone Marrow-Derived RIPK3 Mediates Kidney Inflammation in Acute Kidney Injury.

Abstract

Receptor-interacting protein kinase 3 (RIPK3), a component of necroptosis pathways, may have an independent role in inflammation. It has been unclear which RIPK3-expressing cells are responsible for the anti-inflammatory effect of overall <i>Ripk3</i> deficiency and whether <i>Ripk3</i> deficiency protects against kidney inflammation occurring in the absence of tubular cell death. We used chimeric mice with bone marrow from wild-type and <i>Ripk3</i>-knockout mice to explore RIPK3's contribution to kidney inflammation in the presence of folic acid-induced acute kidney injury AKI (FA-AKI) or absence of AKI and kidney cell death (as seen in systemic administration of the cytokine TNF-like weak inducer of apoptosis [TWEAK]). Tubular and interstitial cell RIPK3 expressions were increased in murine AKI. <i>Ripk3</i> deficiency decreased NF-<i>κ</i>B activation and kidney inflammation in FA-AKI but did not prevent kidney failure. In the chimeric mice, RIPK3-expressing bone marrow-derived cells were required for early inflammation in FA-AKI. The NLRP3 inflammasome was not involved in RIPK3's proinflammatory effect. Systemic TWEAK administration induced kidney inflammation in wild-type but not <i>Ripk3</i>-deficient mice. In cell cultures, TWEAK increased RIPK3 expression in bone marrow-derived macrophages and tubular cells. RIPK3 mediated TWEAK-induced NF-<i>κ</i>B activation and inflammatory responses in bone marrow-derived macrophages and dendritic cells and in Jurkat T cells; however, in tubular cells, RIPK3 mediated only TWEAK-induced <i>Il-6</i> expression. Furthermore, conditioned media from TWEAK-exposed wild-type macrophages, but not from <i>Ripk3</i>-deficient macrophages, promoted proinflammatory responses in cultured tubular cells. RIPK3 mediates kidney inflammation independently from tubular cell death. Specific targeting of bone marrow-derived RIPK3 may limit kidney inflammation without the potential adverse effects of systemic RIPK3 targeting.