Abstract Body: We previously demonstrated that microglial ADAM17 plays a role in regulating salt-sensitive hypertension and the associated inflammatory response. More recently, we observed that deletion of ADAM17 from microglia mitigates neuronal hyperactivity and sympatho-excitation in salt-sensitive hypertension. However, the precise mechanisms underlying neuron-microglia communication remain unclear. We hypothesize that neuronal CX3CL1 promotes the activation of CX3CR1 in microglia, leading to the upregulation of ADAM17 in microglia. To assess the link between CX3CL1/CX3CR1 and ADAM17 upregulation, a microglia cell line (BV2) was used. CX3CL1 (50 nM) treatment of BV2 cells led to a significant upregulation of CX3CR1 (3.2 ±0.6 vs. 1.0 ±0.1, t- test P<0.05) and the mature form of ADAM17 (188 ±38 vs. 1.0 ±0.6, t-test P<0.05) while the pro-form of ADAM17 was downregulated (0.45 ±0.14 vs. 1 ±0.05, P<0.05). Together, these data confirm that CX3CL1 mediates the upregulation of ADAM17 in microglia activation. To further investigate the CX3CL1/CX3CR1 impact in microglial activation during salt-sensitive hypertension, we extended our study to C57BI/6J male mice (3-month-old, n=10) implanted with telemetry probes for monitoring BP. One week following baseline BP recording, mice received a deoxycorticosterone acetate pellet subcutaneously (DOCA, 50 mg) plus 1% salt in drinking water. Following the establishment of hypertension (4 days post DOCA implantation) mice were infused with CX3CR1 antagonist (AZD8797, 480 µg/kg/d) for 2 weeks using osmotic pump (100 µl ICV). At the end of treatment, mice were euthanized, and their brains were collected. Baseline mean arterial pressure (MAP) was not different among groups (103 ±4 vs. 101 ±3 mmHg) and all mice developed hypertension following DOCA implantation, (MAP: 130 ±2 mmHg). After confirming hypertension, mice were divided into Vehicle and AZD8797 treatment groups (n=5/group). Interestingly, following ICV infusion, the AZD8797 group showed a blunted hypertension compared to the vehicle group (MAP: 128 ±5 vs. 146 ±5 mmHg, t-test, p<0.05). Together, these findings suggest that CX3CR1 in microglia is critical for the development of salt-sensitive hypertension by regulating ADAM17 expression.