CX3CL1-CX3CR1 pathway mediates hyperthermia-induced microglial processes retraction

In infants, high fever is associated with robust microglial morphological changes, including process retraction and soma enlargement, which contribute to fever-induced seizures. The molecular mechanisms underlying dynamic process retraction during hyperthermia remain poorly understood. Using a hyperthermia-induced microglial activation model in postnatal day 8 mice, we identified the CX₃CL1-CX₃CR1 interaction as a key regulator of process retraction. The CX₃CL1 is mainly cleaved by metalloproteases ADAM10 under hyperthermia stimulation. Pharmacological inhibition or genetic knockdown of ADAM10 prevented microglial process retraction. Hyperthermia is known to induce the release of glutamate and activation of the NMDA receptor. We found that NMDA mimicked the effects of hyperthermia on microglia, while the NMDA blocker MK801 attenuated hyperthermia-induced process retraction. Collectively, our findings suggest that the CX₃CL1-CX₃CR1 pathway plays a critical role in mediating dynamic microglial process retraction in response to hyperthermia.