Bone Marrow–Derived RIPK3 Mediates Kidney Inflammation in Acute Kidney Injury

Abstract

BackgroundReceptor-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.MethodsWe 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]).ResultsTubular and interstitial cell RIPK3 expressions were increased in murine AKI. Ripk3 deficiency decreased NF-κB 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-κB 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.ConclusionsRIPK3 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.

Regulated cell death pathways in kidney disease

“…Targeting of TWEAK or necroptosis shortened the duration of AKI, and led to improved kidney function and histology 96 h after exposure to folic acid in mice. However, in one study, specific targeting of bone marrow-derived RIPK3 induced an early decrease in kidney inflammation independent of effects on tubule cell death and did not improve kidney function 48 h after administration of folic acid 65 , suggesting that RIPK3 might have a dual role in FA-AKI by promoting both early inflammation through its function in innate immune cells and later tubule cell necroptosis in response to inflammatory cytokines through its function in tubular cells. FA-AKI has also been used as a model to explore the effect of ferroptosis on the lipidome 103 , 117 , 175 .…”

“…However, additional canonical and non-canonical pathways for RIPK3 activation exist that do not require RIPK1 63 , 64 (Fig. 3c ); moreover, RIPK3 can promote inflammatory responses independent of necroptosis 65 , 66 . In kidney cells, inhibition of caspases prevents apoptosis, but may lead to RIPK1-mediated necroptosis, as observed in a model of cytokine-induced tubule cell death 18 , 67 .…”

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

“…Numerous studies indicate that macrophages are a major contributor to the inflammatory response of AKI ( Huen and Cantley, 2017 ; Martin-Sanchez et al, 2022 ). Macrophage-induced inflammatory and fibrotic responses are also key drivers of renal fibrosis, which will enhance the progression of CKD ( Chen et al, 2022 ; Zhou et al, 2022 ).…”

Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy

“…RIPK3-caspase is crucial in the procession of macrophage differentiation ( 79 ), while how necroptosis mediated NLRP3 inflammasome activation, and mechanisms underly AKI to CKD progression remain unclear. As in tubular cells, TWEAK (TNF-like weak inducer of apoptosis) increased RIPK3 expression in macrophages however there is nothing known about RIPK1 ( 80 ). Macrophages conditional knockout mice also are involved in decreasing expression of MCP-1, IL-6, IL-1β like in renal tubular cells.…”

“…Macrophages conditional knockout mice also are involved in decreasing expression of MCP-1, IL-6, IL-1β like in renal tubular cells. Moreover, RIPK3 in macrophages promotes NF- κ B–dependent release of proinflammatory cytokines and activates the NF- κ B signaling pathway, in turn, promoting macrophage-tubular crosstalk that recruits inflammatory responses from tubular cells ( 80 ). Evidence has shown that necroptosis plays a crucial part in the early progression of multiple types of AKI ( 81 , 82 ).…”