A dermo-hypothalamic axis driven by TNF-α mediates sleep disturbances in psoriasis

Sleep disturbances are a debilitating feature of psoriasis, but whether they arise from itching or from direct effects of inflammation on the brain remains unclear. Here we show, using clinical data and a mouse model of psoriasis-like inflammation, that affected animals exhibit marked wakefulness and fragmented non-rapid eye movement sleep, even when itching is eliminated. This sleep disruption is linked to overactivity of wake-promoting neurons in a brain region called the anterior hypothalamic area. We find evidence of a local inflammatory response in this region, including activation of microglia and elevated levels of the signaling protein tumor necrosis factor-alpha. Directly delivering an inhibitor of this protein into the anterior hypothalamic area significantly restores normal sleep. These findings reveal a direct pathway from skin inflammation to sleep-regulating brain circuits and identify tumor necrosis factor-alpha as a potential target for treating insomnia in psoriasis. Clinical data and a mouse model of psoriasis reveal a direct pathway from skin inflammation to sleep-regulating brain circuits, identifying tumor necrosis factor-alpha as a potential therapeutic target for psoriasis-associated insomnia.