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 Ripk3 deficiency and whether Ripk3 deficiency protects against kidney inflammation occurring in the absence of tubular cell death.

We used chimeric mice with bone marrow from wild-type and Ripk3-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. Ripk3 deficiency decreased NF-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 Ripk3-deficient mice. In cell cultures, TWEAK increased RIPK3 expression in bone marrow–derived macrophages and tubular cells. RIPK3 mediated TWEAK-induced NF-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 Il-6 expression. Furthermore, conditioned media from TWEAK-exposed wild-type macrophages, but not from Ripk3-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.

受体相互作用蛋白激酶 3 (RIPK3) 是坏死性凋亡途径的一个组成部分，可能在炎症中具有独立的作用。目前尚不清楚哪些表达 RIPK3 的细胞负责整体Ripk3缺陷的抗炎作用，以及Ripk3缺陷是否可以防止在没有肾小管细胞死亡的情况下发生肾脏炎症。

我们使用含有野生型和Ripk3基因敲除小鼠骨髓的嵌合小鼠来探索 RIPK3 在叶酸诱导的急性肾损伤 AKI (FA-AKI) 或不存在 AKI 和肾细胞死亡的情况下对肾脏炎症的贡献（如见于细胞因子 TNF 样弱细胞凋亡诱导剂 [TWEAK] 的全身给药）。

小鼠 AKI 中的小管和间质细胞 RIPK3 表达增加。Ripk3缺陷减少 NF-FA-AKI 中的 B 激活和肾脏炎症，但不能预防肾衰竭。在嵌合小鼠中，表达 RIPK3 的骨髓来源细胞是 FA-AKI 早期炎症所必需的。NLRP3 炎性体不参与 RIPK3 的促炎作用。全身性 TWEAK 给药在野生型而非Ripk3缺陷小鼠中诱导肾脏炎症。在细胞培养物中，TWEAK 增加了骨髓来源的巨噬细胞和肾小管细胞中 RIPK3 的表达。RIPK3 介导的 TWEAK 诱导的 NF-骨髓来源的巨噬细胞和树突状细胞以及 Jurkat T 细胞中的 B 活化和炎症反应；然而，在肾小管细胞中，RIPK3 仅介导 TWEAK 诱导的Il-6表达。此外，来自 TWEAK 暴露的野生型巨噬细胞而非Ripk3缺陷型巨噬细胞的条件培养基促进了培养的肾小管细胞的促炎反应。

RIPK3 独立于肾小管细胞死亡介导肾脏炎症。骨髓来源的 RIPK3 的特异性靶向可能会限制肾脏炎症，而不会产生全身性 RIPK3 靶向的潜在副作用。