CX3CL1 deficiency ameliorates acute kidney injury by inhibiting macrophage mitochondrial dysfunction and mtDNA-cGAS-STING signaling.

Dysregulated mitochondrial dynamics and macrophage-driven inflammation are essential contributors to the pathogenesis of acute kidney injury (AKI). Although the chemokine CX3CL1 has been associated with inflammatory responses, its role in AKI, particularly in regulating macrophage polarization and mitochondrial function, remains unclear. In this study, we investigated the therapeutic potential of CX3CL1 inhibition in a lipopolysaccharide (LPS)-induced AKI model. Our results found that CX3CL1 deficiency could significantly ameliorate renal dysfunction and attenuate inflammatory responses. RNA sequencing revealed that CX3CL1 deficiency alters macrophage subpopulations and gene expression profiles in the kidney, particularly affecting pathways related to immune responses and mitochondrial function. Mechanistically, the absence of CX3CL1 promotes macrophage polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. Furthermore, CX3CL1 inhibition improves mitochondrial dynamics, alleviates mitochondrial dysfunction, and reduces oxidative stress and mitochondrial DNA (mtDNA) leakage, thereby preserving mitochondrial integrity. Notably, CX3CL1 knockdown suppresses activation of the cGAS-STING pathway, a key mediator of inflammation triggered by cytosolic mtDNA. We also observed that these effects appear to be mediated through stabilization of mitochondrial transcription factor A (TFAM). Collectively, these findings identify CX3CL1 as an essential regulator of macrophage mitochondrial function and inflammation in AKI, offering a potential therapeutic target for mitigating kidney injury.