PD-1-Dependent Modulation of Sensory Neurons by a Staphylococcus epidermidis Lipoteichoic Acid Drives Analgesia

The immune checkpoint receptor PD-1, traditionally known for suppressing T-cell activation, is also expressed in peripheral sensory neurons where it limits excitability, but the physiological contexts in which neuronal PD-1 is engaged remain poorly defined. We previously identified a purified Staphylococcus epidermidis lipoteichoic acid analog (SELTA) that rapidly alleviates pelvic pain in mice. Here, we investigated whether SELTA functions as an exogenous activator of neuronal PD-1 and whether PD-1 is required for its analgesic effects. SELTA increased Pdcd1 transcripts and PD-1 protein in dorsal root ganglion (DRG) neurons and prostate-innervating sensory fibers, and colocalized with TLR2 at neuronal membranes where it enhanced PD-1 Y248 phosphorylation. In primary DRG cultures, SELTA suppressed ATP-evoked Ca{superscript 2} responses, indicating reduced neuronal excitability. This effect was abolished by PD-1 neutralization but restored when neutralization was blocked by a PD-1 control peptide, demonstrating both PD-1 dependence and specificity. In male mice with chronic pelvic allodynia induced by experimental autoimmune prostatitis, intraurethral SELTA produced robust, concentration-dependent, and repeatable reductions in tactile hypersensitivity. Sensory neuron-specific PD-1 conditional knockout mice showed normal baseline behavior but failed to respond to SELTA, confirming that PD-1 expression in nociceptors is essential for SELTA-mediated analgesia. These findings identify SELTA as a commensal-derived activator of neuronal PD-1 signaling. Through TLR2 engagement, PD-1 phosphorylation, and suppression of excitatory calcium signaling, SELTA attenuates nociceptor activation and reduces pelvic pain. This mechanism highlights neuronal PD-1 as a modifiable checkpoint pathway and a promising non-opioid target for chronic pain therapy.