PT - JOURNAL ARTICLE AU - Eva Soto-Tinoco AU - Esteban Santacruz AU - María del Carmen Basualdo-Sigales AU - Natalí N. Guerrero-Vargas AU - Ruud M Buijs TI - Time-of-day-dependent gating of the liver-spinal axis initiates an anti-inflammatory reflex in the rat AID - 10.1523/ENEURO.0463-20.2020 DP - 2020 Nov 17 TA - eneuro PG - ENEURO.0463-20.2020 4099 - http://www.eneuro.org/content/early/2020/11/17/ENEURO.0463-20.2020.short 4100 - http://www.eneuro.org/content/early/2020/11/17/ENEURO.0463-20.2020.full AB - The autonomic nervous system (ANS) modulates the immune response through the engagement of an anti-inflammatory reflex. There is controversy regarding which efferent branch of the ANS, sympathetic or parasympathetic, downregulates the intensity of the inflammatory response. Furthermore, how information about the immune status of the body reaches the central nervous system (CNS) to engage this reflex remains unclear.The present study demonstrates the existence of a liver-spinal axis that conveys early circulating inflammatory information to the CNS and serves as the afferent arm of a sympathetic anti-inflammatory reflex. Furthermore, brainstem and spinal cord visceral sensory neurons show a time-of-day-dependent sensitivity to the incoming inflammatory information, in particular, prostaglandins. Consequentially, the liver-spinal axis promotes the retention of tumor necrosis factor α (TNFα) in the liver and spleen during the resting period, resulting in low plasmatic TNFα levels. Consistently, low sensitivity for LPS during the active period promotes the release of TNFα from the organs into the circulation, resulting in high plasmatic TNFα levels. The present novel findings illustrate how the time-of-day-dependent activation of the liver-spinal axis contributes to the daily fluctuations of the inflammatory response.Significance Statement The anti-inflammatory reflex is a survival mechanism essential for homeostasis. An out-of-control inflammatory process is detrimental to the individual and it is the cornerstone of many chronic diseases. It has been suggested that the sensory vagus nerve works as the afferent arm of this reflex arc, detecting circulating cytokines in order to start the anti-inflammatory reflex. The present study provides strong evidence of an additional afferent arm, which we have named the liver-spinal axis, that senses early inflammatory mediators that precede cytokine release into circulation. As an additional layer of complexity, inflammation has adapted to the light-dark cycle. We demonstrate that the anti-inflammatory reflex is time-of-day-dependent, synchronizing the peak of the inflammatory response to when it is most likely needed.