Time-of-Day-Dependent Gating of the Liver-Spinal Axis Initiates an Anti-Inflammatory Reflex in the Rat

Abstract

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 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 in response to lipopolysaccharide (LPS) 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 (PG). 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.

Acute Inhibition of Inflammation Mediated by Sympathetic Nerves: The Inflammatory Reflex

“…Our data showed that rats with the hepatic sympathetic nerves severed responded to intravenous LPS with IL-10 and TNF levels no different to those of sham-operated animals [ 34 ], indicating that these nerves are not necessary for the acute reflex control of systemic inflammation. These results deviated from those reported by Soto-Tinoco and colleagues, where animals with denervated livers responded to LPS with an exaggerated TNF release [ 54 ]. It is likely that several differences in experimental approach underlie these discrepancies.…”

“…While extensive research work has been done on the pathways composing the efferent arm of the inflammatory reflex, much less is known about the afferent arm and the central integrative pathways. Recent studies have described the important contributions of the carotid body and of a liver-spinal axis as possible sensory arms of the inflammatory reflex [ 54 , 58 ]; however, the contributions from the vagus nerve and circulating humoral factors, including immune cells and their by-products, also need to be considered. Further, studies are necessary to delineate the inflammatory reflex and understand how the sympathetic nervous system is involved in the check and balance mechanisms that characterize immune responses, acute and chronic, involving innate and adaptive immunity.…”

Divergent splanchnic sympathetic efferent nerve pathways regulate interleukin‐10 and tumour necrosis factor‐α responses to endotoxaemia

“…Experiments where the sympathetic nerves to the liver were removed (and its vagal innervation also removed by vagotomy) showed no evidence for their involvement in the regulation of either TNF or IL‐10 responses to systemic LPS (Figs 7 and 8). This result was surprising, in view of the recent demonstration by Soto‐Tinoco and colleagues that spinal afferent fibres in the hepatic sympathetic nerves support an early anti‐inflammatory reflex response to systemic LPS (Soto‐Tinoco et al., 2020). Several differences in experimental approach may account for this discrepancy: here, we used a higher dose of systemic LPS (60 vs .…”

“…Section of the hepatic sympathetic nerves has previously been reported to enhance TNF levels in endotoxaemic rats, an effect attributed to interrupting transmission in afferent fibres to the spinal cord (Soto‐Tinoco et al., 2020). In vagotomized animals, we therefore cut the hepatic sympathetic nerves (which include the spinal afferent supply, completing liver denervation), and compared these with vagotomized animals given sham hepatic nerve section.…”

“…Second, the present study followed our previous work (Komegae et al., 2018; Martelli, Yao, Mancera et al., 2014; Martelli, Yao, McKinley et al., 2014; Martelli et al., 2019) in using a single, mid‐range dose of LPS (<1% of the lethal dose in rats (Nezic et al., 2009)). Others have used lower (Meltzer et al., 2003, 2004; Soto‐Tinoco et al., 2020) or higher (Borovikova et al., 2000; Meltzer et al., 2003) doses. The cytokine responses seen to 60 µg/kg LPS in the present study were clearly amenable to modulation by neural influences, but we cannot say whether other mechanisms might apply in the response to lower or higher doses.…”