Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painful neuropathy

Peripheral nerves and their axons are shielded by the blood-nerve and the myelin barrier. Understanding of how these barriers impact nociception is limited, particularly in neuropathy. Here, we identified a regulatory axis of the tight junction protein claudin-12 sex-dependently coordinating perineurial and myelin barrier integrity. Claudin-12 regulated selected tight junction proteins via sonic hedgehog (SHH) and thereby controlled pain sensation and mechanical nociception. In nerve biopsies, only patients with painful polyneuropathy lost claudin-12 in Schwann cells independently of the presence of inflammation or the extent of fiber loss. Global KO of Cldn12 selectively increased perineurial/myelin barrier leakage, damaged tight junction protein expression and morphology and amplified mechanical hypersensitivity in naive and neuropathic male mice. Other barriers and neurological function remained intact. In vitro transfection studies documented claudin-12 plasma membrane localisation without interaction with other tight junction proteins or intrinsic sealing properties. Rather, claudin-12 had a regulatory tight junction protein function via the morphogen SHH in vivo as observed in Cldn12-KO and after local siRNA application. Female mice were protected against mechanical hypersensitivity, barrier opening, tight junction protein loss and SHH downregulation. Collectively, these studies reveal the critical role of claudin-12 maintaining the myelin barrier and highlight restoration of the claudin-12/SHH pathway as a potential target for painful neuropathy.