Comparison of anti-inflammatory influences of the splanchnic sympathetic nerve with those of the hypothalamic-pituitary-adrenal (HPA) axis during systemic inflammation

Abstract

Branches of the splanchnic sympathetic nerve, that supply several abdominal organs including adrenals, provide the efferent neural pathway for reflex dampening of systemic inflammation (SI). In response to SI, the splanchnic nerves not only suppress secretion of the pro-inflammatory cytokine tumour necrosis factor-α (TNF) but drive release of the anti-inflammatory cytokine interleukin-10 (IL-10) (1,2,3). Recently we showed that the adrenal branch plays a major role in driving IL-10 secretion (3), while distal branches to other organs (e.g. spleen) suppress TNF secretion from immune cells (2,3). Glucocorticoid secretion resulting from activation of the HPA axis during SI is also anti-inflammatory. The present study compares the anti-inflammatory role of the adrenal cortex with that of the splanchnic nerve and adrenal medulla following i.v. lipopolysaccharide (LPS; 60 μg/kg) in urethane-anesthetized male rats. Plasma TNF and IL-10 levels sampled at 90 min after LPS injection were measured by ELISA. We hypothesized that the anti-inflammatory action of the splanchnic nerve differs from that of adrenal corticosteroids during SI. Gender differences were not investigated. We compared effects on endotoxin stimulated IL-10 and TNF secretion of cutting bilaterally (i) adrenal nerves, n=6, (ii) splanchnic nerves, n = 5, (iii) bilateral adrenalectomy, n = 8, (iv) combined adrenalectomy and splanchnic nerve cuts, n = 7, and (v) sham surgery, n = 5. As expected, TNF levels in response to LPS increased after cutting splanchnic (17.1 ± 2.5 ng/ml, mean ± SEM, p < 0.001) or adrenal (12.9 ± 3.8 ng/ml, p < 0.05) nerves compared with sham operated rats (3.9 ± 1.3 ng/ml). Adrenalectomy which reduces circulating adrenaline as well as corticosterone levels, resulted in greater plasma [TNF] (36.4 ± 5.2 ng/ml, p < 0.001), while combined splanchnic denervation and adrenalectomy further increased the TNF level to 61.3 ± 12. 4 ng/ml. Regarding plasma IL-10 levels, cutting either splanchnic or adrenal nerves alone reduced LPS-induced plasma IL-10 from 0.9 ± 0.2 ng/ml (sham) to 0.2 ± 0.1 and 0.3 ± 0.1 ng/ml respectively (both p < 0.05), whereas bilateral adrenalectomy alone (1.1 ± 0.1 ng/ml) or combined with splanchnic denervation (0.6 ± 0.1 ng/ml) did not. We conclude that glucocorticoids strongly suppress both pro- and anti-inflammatory cytokines. However, splanchnic sympathetic nerves are more selective, enhancing release of the anti-inflammatory cytokine IL-10, via adrenaline release, while suppressing pro-inflammatory cytokines such as TNF. References. (1) Martelli, D. et al., J Physiol. 592: 1677-86, 2014. (2) Martelli, D. et al., Am J Physiol Regul Integr Comp Physiol. 316: R235-242, 2019. (3) McKinley, M.J. et al., J Physiol. 600: 4521-36, 2022. NHMRC of Australia This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.