Bone Marrow–Derived RIPK3 Mediates Kidney Inflammation in Acute Kidney Injury
Authors: Martin-Sanchez Diego , Guerrero-Mauvecin Juan , Fontecha-Barriuso Miguel , Mendez-Barbero Nerea , Saiz Maria Laura , Lopez-Diaz Ana M. , Sanchez-Niño Maria D. , Carrasco Susana , Cannata-Ortiz Pablo , Ruiz-Ortega Marta , Ortiz Alberto , Sanz Ana B. 
Published: January 2022

Significance Statement

Receptor-interacting protein kinase 3 (RIPK3), a key necroptosis pathway protein, may have an independent role in inflammation. The authors explored RIPK3′s role in kidney inflammation occurring in the presence or absence of kidney cell death and AKI, identifying RIPK3—bone marrow RIPK3 specifically—as a driver of kidney inflammation, even in the absence of tubular cell death or kidney failure. Experiments in chimeric mice and cell culture identified IL-6 as a key RIPK3-regulated mediator and showed that RIPK3 expression by bone marrow cells recruits proinflammatory responses in tubular cells. These findings identify bone marrow RIPK3 as a key mediator and potential therapeutic target in conditions characterized by kidney inflammation. Strategies aimed at targeting bone marrow RIPK3 may preserve therapeutic efficacy while decreasing potential systemic consequences of RIPK3 inhibition.

Background

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.

Methods

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]).

Results

Tubular 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.

Conclusions

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.