The voltage-gated proton channel Hv1 is a recently cloned ion channel that rapidly removes protons from depolarized cytoplasm and is highly expressed in the immune system. In the CNS, Hv1 is expressed by resting microglia but not neurons or astrocytes in the mouse brain. Microglial Hv1 regulates intracellular pH and aids in NOX2-dependent generation of reactive oxygen species (ROS). Thus, Hv1 is a unique target for controlling multiple NOX activities and ROS production. Recently, we observed rapid and persistent upregulation of Hv1 in the injured spinal cord after a moderate contusion; the remained up to 8 months post-injury1,2. Our revelation studies point to an acute neuroprotection phenotype when Hv1 is genetically deleted including infiltrating immune cells, indicating a critical role of Hv1 signaling in SCI pathophysiology1. However, neither the precise cellular mechanisms underlying this finding nor critical role of Hv1 in the pathophysiology of SCI are fully understood. We hypothesize that microglial Hv1 functions as a key mechanism in neuroinflammation, thus affecting long-term neurological outcome after SCI.