ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Extracellular CIRP Augments Inflammation in Acute Kidney Injury via NKG2D-positive Macrophages
Provisionally accepted
- Feinstein Institute for Medical Research, New York, United States
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The mechanism by which extracellular cold-inducible RNA-binding protein (eCIRP) aggravates renal ischemia/reperfusion (RIR) injury leading to acute kidney injury (AKI) is poorly understood. The natural killer group 2D (NKG2D) receptor and its ligand MULT-1 are key immunoregulatory mechanisms promoting responses to damaged and inflamed cells. We subjected wild-type and CIRP−/− mice to RIR. We then used immunohistochemistry (IHC), flow cytometry, and Western blotting to assess NKG2D and MULT-1 in kidney tissues, macrophages, and renal tubular epithelial cells (RTECs), and ELISA to assess TNFα and IL-6. The expression levels of NKG2D and its ligand MULT-1 were significantly elevated in wild-type mice subjected to RIR compared with sham. In contrast, CIRP−/− mice exhibited markedly reduced expression of both NKG2D and MULT-1 after RIR compared to wild-type mice. In vitro, eCIRP stimulated the expression of NKG2D in peritoneal macrophages and of MULT-1 in RTECs. Treatment of eCIRP-stimulated peritoneal macrophage and RTEC co-cultures with an NKG2D-neutralizing antibody significantly and markedly downregulated supernatant levels of TNFα and IL-6. In conclusion, eCIRP induces NKG2D+ macrophages and MULT-1+ RTECs, and their interaction further increases the inflammatory response. Targeting the NKG2D/MULT-1 may reduce RIR-induced inflammation and thus attenuate AKI.
Keywords: AKI, eCIRP, Macrophages, MULT-1, NKG2D, RIR, RTECs
Received: 10 Sep 2025; Accepted: 16 Dec 2025.
Copyright: © 2025 Zhang, JIN, TAN, Wang and Brenner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Max Brenner
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