Anti-inflammatory reflex action of splanchnic sympathetic nerves is distributed across abdominal organs

Abstract

The splanchnic anti-inflammatory pathway has been proposed as the efferent arm of the inflammatory reflex. Although much evidence points to the spleen as the principal target organ where sympathetic nerves inhibit immune function, a systematic study to locate the target organ(s) of the splanchnic anti-inflammatory pathway has not yet been made. In anesthetized rats made endotoxemic with lipopolysaccharide (LPS, 60 µg/kg iv), plasma levels of tumor necrosis factor-α (TNF-α) were measured in animals with cut (SplancX) or sham-cut (Sham) splanchnic nerves. We confirm here that disengagement of the splanchnic anti-inflammatory pathway in SplancX rats (17.01 ± 0.95 ng/ml, mean ± SE) strongly enhances LPS-induced plasma TNF-α levels compared with Sham rats (3.76 ± 0.95 ng/ml). In paired experiments, the responses of SplancX and Sham animals were compared after the single or combined removal of organs innervated by the splanchnic nerves. Removal of target organ(s) where the splanchnic nerves inhibit systemic inflammation should abolish any difference in LPS-induced plasma TNF-α levels between Sham and SplancX rats. Any secondary effects of extirpating organs should apply to both groups. Surprisingly, removal of the spleen and/or the adrenal glands did not prevent the reflex splanchnic anti-inflammatory action nor did the following removals: spleen + adrenals + intestine; spleen + intestine + stomach and pancreas; or spleen + intestine + stomach and pancreas + liver. Only when spleen, adrenals, intestine, stomach, pancreas, and liver were all removed did the difference between SplancX and Sham animals disappear. We conclude that the reflex anti-inflammatory action of the splanchnic nerves is distributed widely across abdominal organs.

Time Course of Hemodynamic Responses to Different Doses of Lipopolysaccharide in Unanesthetized Male Rats

“…Concerning the heart rate, we observed that all doses tested increased this hemodynamic parameter, over time, supporting previous observation (Altavilla et al, 2002). Moreover, in agreement with previous studies (Martelli et al, 2019), our findings demonstrated that the lowest dose tested (0.06 mg/kg) reduces the mean arterial pressure over time. However, it has been described a transient increase in mean arterial pressure, 2 and 3 h after LPS administration, with the return of this hemodynamic parameter to baseline, 4–6 h later, using the same dose (0.06 mg/kg) (Martelli et al, 2014).…”

“…However, it has been described a transient increase in mean arterial pressure, 2 and 3 h after LPS administration, with the return of this hemodynamic parameter to baseline, 4–6 h later, using the same dose (0.06 mg/kg) (Martelli et al, 2014). Apropos, this dose of LPS has been extensively used in rats for investigating the mechanisms involved in the inflammatory reflex pathway (Martelli et al, 2014, 2019; Komegae et al, 2018), as well as for evaluating the baroreflex regulation during systemic inflammation (Tohyama et al, 2018).…”

Sympathetic nerves control bacterial clearance

“…We previously demonstrated in rats that the splanchnic nerve-mediated anti-inflammatory action is distributed across the abdominal organs innervated by that sympathetic nerve, including the spleen, intestines, stomach, pancreas, liver and adrenal medulla 16 . While the splanchnic nerves drive the release of catecholamines from the adrenal medulla 17 , the reflex survives adrenalectomy, indicating that direct release of neurotransmitters from sympathetic nerve terminals suppresses inflammation 16 . We infer that removal of the braking influence of the splanchnic nerves enhances the capacity to sequester and kill circulating bacteria by phagocytic and cytotoxic cells distributed broadly in the abdominal viscera.…”

Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity

“…It was already demonstrated that septic patients show a loss of sympathetic splenic nerves, indicating a regulating role in disease [77]. Nevertheless, recent insights also show that the spleen might not be as essential as previously believed, since the anti-inflammatory properties of splanchnic nerve stimulation are spread across other abdominal organs such as the liver and adrenal glands [78].…”