Nogo receptor antagonist LOTUS exerts suppression on axonal growth-inhibiting receptor PIR-B

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown. In this study, protein-protein interactions analyses found that LOTUS binds to PIR-B and abolishes Nogo-binding to PIR-B completely. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that PIR-B is expressed in dorsal root ganglions (DRGs) from wild-type and Ngr1-deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo-induced growth cone collapse and neurite outgrowth inhibition in Ngr1-deficient DRG neurons were neutralized by PIR-B function-blocking antibodies, indicating that these Nogo-induced phenomena were mediated by PIR-B. Our data show that LOTUS negatively regulates a PIR-B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR-B. This may lead to an improvement in the defective regeneration of axons following injury.