Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anesthesia

Abstract

Following an immune challenge, there is two-way communication between the nervous and immune systems. It is proposed that a neural reflex--the inflammatory reflex--regulates the plasma levels of the key proinflammatory cytokine TNF-α, and that its efferent pathway is in the splanchnic sympathetic nerves. The evidence for this reflex is based on experiments on anesthetized animals, but anesthesia itself suppresses inflammation, confounding interpretation. Here, we show that previous section of the splanchnic nerves strongly enhances the levels of plasma TNF-α in conscious rats 90 min after they received intravenous LPS (60 μg/kg). The same reflex mechanism, therefore, applies in conscious as in anesthetized animals. In anesthetized rats, we then determined the longer-term effects of splanchnic nerve section on responses to LPS (60 μg/kg iv). We confirmed that prior splanchnic nerve section enhanced the early (90 min) peak in plasma TNF-α and found that it reduced the 90-min peak of the anti-inflammatory cytokine IL-10; both subsequently fell to low levels in all animals. Splanchnic nerve section also enhanced the delayed rise in two key proinflammatory cytokines IL-6 and interferon γ. That enhancement was undiminished after 6 h, when other measured cytokines had subsided. Finally, LPS treatment caused hypotensive shock in rats with cut splanchnic nerves but not in sham-operated animals. These findings demonstrate that reflex activation of the splanchnic anti-inflammatory pathway has a powerful and sustained restraining influence on inflammatory processes.

Deletion of muscarinic type 1 acetylcholine receptors alters splenic lymphocyte functions and splenic noradrenaline concentration

“…For this purpose, we used M1KO and heterozygous AChE+/− mice, since homozygous acetylcholinesterase knockout mice do not develop normally under standard conditions [26]. The spleen was chosen because, as mentioned, it does not have cholinergic innervation [3][4][5].…”

“…However, the spleen, a major secondary immune organ, seems to be an exception, since no parasympathetic innervation has been detected in this organ. In fact, no connection between cholinergic vagal fibers with retrograde labeled fibers from the spleen could be detected either in the suprarenal ganglia, the left coeliac ganglion or the superior mesenteric ganglia [3][4][5]. Conversely, the sympathetic innervation of the spleen is clearly established.…”

“…Experiments based on electrophysiological and pharmacological approaches have clearly shown that noradrenaline (NA), the main sympathetic neurotransmitter, can influence the activity of immune cells in the spleen [4,[7][8][9][10]. On the other hand, the immune response itself can reciprocally influence sympathetic activity in the spleen [8,11,12].…”

The Influence of Systemic Immune Response and Sleep Modulation on the Secondary Effects of Traumatic Brain Injury in the Rodent Model

“…Recent studies have suggested that the autonomic nervous system, as a regulator of homeostatic processes, modulates peripheral macrophage activation through the activity of the splenic nerve (Martelli et al, 2014). Specifically, nerve terminals in the white pulp of the spleen discharge norepinephrine to activate ␤-adrenergic receptors of nearby T cells.…”

“…Recent evidence suggests that nAChR␣7 activation in the thalamic reticular nucleus increases both spindle oscillation and the duration of non-REM sleep (Ni et al, 2016). This is particularly interesting given indications that short-term sleep deprivation and the associated increase in slow-wave sleep (SWS) exhibit neuroprotective effects after TBI (Martinez-Vargas et al, 2012). Morawska et al (2016) found that, after TBI, both sleep-restricted rats and rats in which sleep was induced pharmacologically showed average increases in SWS compared with untreated controls.…”