Sphingomyelin synthase 1 as a potential upstream amplifier of microglial CSF1R signaling in neuropathic pain

Neuropathic pain is a debilitating chronic condition sustained by maladaptive neuroimmune interactions within the central nervous system, with microglial activation in the spinal dorsal horn serving as a critical driver of pain initiation and chronification. Within this framework, microglial activation mediated by colony-stimulating factor 1 receptor (CSF1R) signaling has emerged as a pathway that is both necessary and sufficient for the development and maintenance of neuropathic pain; however, the upstream mechanisms that determine CSF1R membrane availability and signaling intensity in microglia remain poorly defined. Here, we propose the hypothesis that sphingomyelin synthase 1 (SMS1) functions as a metabolic gatekeeper that amplifies microglial CSF1R signaling by regulating diacylglycerol (DAG)/protein kinase D (PKD)-dependent receptor trafficking. Following peripheral nerve injury, SMS1 expression is upregulated in spinal microglia, leading to increased Golgi-associated DAG production and subsequent PKD activation. Activated PKD promotes vesicular transport of CSF1R from the Golgi apparatus to the plasma membrane, thereby increasing CSF1R surface density and prolonging receptor signaling. Enhanced CSF1R membrane availability amplifies CSF1-driven microglial proliferation and neuroinflammatory signaling, ultimately facilitating synaptic dysregulation and persistent pain hypersensitivity. This hypothesis establishes a direct mechanistic link between sphingolipid metabolism and microglial neuroimmune signaling and identifies SMS1 as a previously unrecognized upstream regulator of neuropathic pain. Targeting SMS1 may therefore represent a novel therapeutic strategy that modulates microglial activation while avoiding the systemic immune suppression associated with direct CSF1R blockade. If validated, this lipid-regulated trafficking mechanism may have broader implications for other microglia-dependent disorders of the central nervous system.