Kidney-resident macrophages limit toxin-induced inflammation through their hallmark functions

The inflammatory phenotype of acute kidney injury (AKI), characterized by interstitial infiltration of immune cells, arises due to nephrotoxic agents. However, it does not pose the same risk of occurrence and progression for everyone, suggesting that the amplification or attenuation of disease depends on the unique immunological status of each kidney. Here, our study investigated the regulatory role of kidney-resident macrophages (KRMs) in the induction and progression of toxin-induced AKI.

To explore this, mice were administered standard pellet chow supplemented, or not, with 0.2% adenine. We injected antibodies against the colony-stimulating factor 1 receptor to selectively depleted KRMs while preserving other kidney-infiltrating macrophages (KiMs) over an extended period owing to different kinetics of KRMs and KiMs.

During the KRM-free period, apoptotic cells accumulated in the interstitium, largely due to the lack of AXL receptor tyrosine kinase, crucial for the efferocytotic function of KRMs. This KRM-free kidney with apoptotic debris induced stress on surrounding tubules, thereby increasing p53 expressing and damage marker (KIM-1)-positive cells. Additionally, KRM-free kidneys presented increased production of chemokine CCL5 from effector CD8⁺ T cells and increased recruitment of CCR5⁺ natural killer cells. This occurred because the remaining KiMs, which expressed lower levels of the immune regulatory protein VISTA than did the KRMs, stimulated the effector CD8⁺ T cells to produce CCL5. The overall alterations in the kidney due to the absence of KRMs ultimately rendered the kidney susceptible to toxin-induced AKI occurrence and progression. Changes in AKI outcomes related to AXL and VISTA expression in kidney mononuclear phagocytes were also observed in human kidney tissues.

Collectively, our findings underscore the hallmark role of KRMs in modulating kidney conditions and mitigating the risk of toxin-induced AKI.