Abstract: TH-OR006
LILRB3 Missense Variants Promote Monocyte-Mediated Inflammation in AKI
Session Information
- AKI Progression and Resolution: Cellular and Molecular Insights
November 06, 2025 | Location: Room 320A, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhang, Weijia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Wei, Chengguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Bigatti, Carolina, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Franchin, Barbara, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Heeger, Peter S., Cedars-Sinai Medical Center, Los Angeles, California, United States
- Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
In our prior study (Nature Medicine, 2025), we identified a cluster of four missense SNPs in the LILRB3 gene that induce a 167-168EP→PS amino acid substitution, significantly associated with death-censored graft loss (DCGL) in African American kidney transplant recipients. These variants were shown to potentiate monocyte-driven adaptive immune activation and ferroptosis, contributing to adverse transplant outcomes. However, the molecular mechanisms underlying these effects remain to be fully elucidated.
Methods
To explore these mechanisms, we generated Pirb knock-in mice—carrying the equivalent mutation in the murine LILRB3 ortholog—on a C57BL/6 background using CRISPR/Cas9 gene editing.
Results
In vitro stimulation of bone marrow-derived macrophages (BMDMs) from wild-type (WT) and mutant mice with LPS revealed significantly elevated expression of pro-inflammatory markers in mutant BMDMs, as measured by qPCR and Western blot. Aurora-based flow cytometry of splenocytes from uninjured mutant mice demonstrated a baseline increase in T cells, alongside reductions in B cell and monocyte populations, suggesting altered immune homeostasis. To evaluate the in vivo functional consequences of the mutation, we employed a renal ischemia-reperfusion injury (IRI) model of acute kidney injury (AKI). Compared to WT mice, the mutant animals exhibited exacerbated AKI characterized by elevated serum BUN levels, upregulation of inflammatory gene expression, and increased immune cell infiltration on histological analysis.
Conclusion
Collectively, these findings suggest that the LILRB3 SNP-driven mutation enhances monocyte-mediated inflammation and T cell activation, thereby amplifying immune responses in AKI. This study provides mechanistic evidence linking LILRB3 genetic variation to heightened immune reactivity and poor kidney transplant outcomes, offering potential avenues for targeted immunomodulatory therapies.
Funding
- NIDDK Support