Divergent splanchnic sympathetic efferent nerve pathways regulate IL-10 and TNF responses to endotoxaemia.

KEY POINTS: An endogenous neural reflex, mediated by the splanchnic, but not other sympathetic nerves, moderates the cytokine response to systemic inflammatory challenge. This reflex suppresses the pro-inflammatory cytokine TNF, while enhancing levels of the anti-inflammatory cytokine IL-10. The reflex enhancement of IL-10 depends on the splanchnic nerve supply to the adrenal gland and on β2 adrenoreceptors, consistent with mediation by circulating adrenaline. After splanchnic nerve section it can be rescued by restoring circulating adrenaline. The reflex suppression of TNF depends on splanchnic nerve branches that innervate abdominal tissues including, but not restricted to, spleen: it is not blocked by adrenal denervation or β2 adrenoreceptor antagonism. Distinct sympathetic efferent pathways are thus responsible for pro- and anti-inflammatory cytokine components of the reflex regulating inflammation.

ABSTRACT: The efferent branches of the splanchnic sympathetic nerves that enhance interleukin-10 (IL-10) and suppress tumour necrosis factor-α (TNF) levels in the reflex response to systemic immune challenge were investigated in anaesthetized, ventilated rats. Plasma levels of TNF and IL-10 were measured 90 min after intravenous lipopolysaccharide (LPS, 60 μg/kg). Splanchnic nerve section, ganglionic blockade with pentolinium tartrate or β2 adrenoreceptor antagonism with ICI 118551 all blocked IL-10 responses. Restoring plasma adrenaline after splanchnic denervation rescued IL-10 responses. TNF responses were disinhibited by splanchnic denervation or pentolinium treatment, but not by ICI 118551. Splanchnic nerve branches were cut individually or in combination in vagotomized rats, ruling out any vagal influence on results. Distal splanchnic denervation, sparing the adrenal nerves, disinhibited TNF but did not reduce IL-10 responses. Selective adrenal denervation depressed IL-10 but did not disinhibit TNF responses. Selective denervation of either spleen or liver did not affect IL-10 or TNF responses, but combined splenic and adrenal denervation did so. Finally, combined section of the cervical and lumbar sympathetic nerves did not affect cytokine responses to LPS. Together, these results show that the endogenous anti-inflammatory reflex is mediated by sympathetic efferent fibres that run in the splanchnic, but not other sympathetic nerves, nor the vagus. Within the splanchnic nerves, divergent pathways control these two cytokine responses: neurally driven adrenaline, acting via β2 adrenoreceptors, regulates IL-10, while TNF is restrained by sympathetic nerves to abdominal organs including the spleen, where non-β2 adrenoreceptor mechanisms are dominant. Abstract figure legend Diagram illustrating two distinct anti-inflammatory reflex pathways. Two distinct anti-inflammatory reflex pathways, both running in the splanchnic sympathetic nerves, are activated by systemic immune challenge. One drives the release of adrenaline, which acts via Î2 2 adrenoreceptors on leukocytes to enhance their release of the anti-inflammatory cytokine, interleukin 10 (IL-10). The second arm suppresses the release of the pro-inflammatory cytokine tumor necrosis factor α (TNF) by immune cells such as macrophages. It is mediated by postganglionic sympathetic nerve fibres that innervate abdominal tissues including the spleen. This action is largely independent of Î2 2 adrenoreceptors. This article is protected by copyright. All rights reserved.