Neuron-derived neuropeptide Y fine-tunes the splenic immune responses

Yu, Jinsong; Xiao, Ke; Chen, Xiaohua; Deng, Lulu; Zhang, Lu; Li, Yue; Gao, Anran; Gao, Jun; Wu, Chengchao; Yang, Xingmei; Zhou, Qiudi; Yang, Jian; Bao, Chenyu; Jiao, Jiaji; Cheng, Sheng; Xu, Weize; Cao, Xiaojian; Guo, Zheng; Dai, Jinxia; Hu, Ji; Fu, Zhenfang; Cao, Gang

doi:10.1016/j.neuron.2022.01.010

Cited by 28 publications

(11 citation statements)

References 68 publications

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“…The main sympathetic neural action on TNF‐generating cells must then depend on non‐β 2 adrenoreceptor transmission, as indicated in Fig. 9; perhaps this is mediated by neurally released noradrenaline acting via non‐β 2 adrenoreceptors and/or by co‐transmitters with an anti‐inflammatory action, such as neuropeptide Y (Bedoui et al., 2003; Straub et al., 2000; Yu et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

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

Martelli

Trevizan‐Baú

McAllen

2022

The Journal of Physiology

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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. 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 tumour necrosis factor‐α (TNF), while enhancing levels of the anti‐inflammatory cytokine interleukin‐10 (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.

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Section: Discussionmentioning

confidence: 99%

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

Martelli

Trevizan‐Baú

McAllen

2022

The Journal of Physiology

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“…To rule out the possibility that HFD causes damages to the gut epithelium and consequently makes a leaky gut, we first measured the expression of three proposed fly cytokines (Unpaired 2 (Upd2), Upd3 and Spaetzle (Spz)) ( Woodcock et al., 2015 ; Yu et al., 2022 ) in the midgut, the head, the abdominal fat body and the Malpighian tubules of flies raised under CD and HFD, but again failed to detect any difference ( Figures 1E–G ). Furthermore, Smurf assay measuring gut permeability ( Rera et al., 2012 ) also argued against a general defect in the integrity of the intestinal epithelium as we did not detect any positive individuals with pathological gut permeability in both CD and HFD conditions (data not shown).…”

Section: Resultsmentioning

confidence: 99%

High-fat diets induce inflammatory IMD/NFκB signaling via gut microbiota remodeling in Drosophila

Wang,

Gu,

et al. 2024

Front. Cell. Infect. Microbiol.

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High-fat diets (HFDs), a prevailing daily dietary style worldwide, induce chronic low-grade inflammation in the central nervous system and peripheral tissues, promoting a variety of diseases including pathologies associated with neuroinflammation. However, the mechanisms linking HFDs to inflammation are not entirely clear. Here, using a Drosophila HFD model, we explored the mechanism of HFD-induced inflammation in remote tissues. We found that HFDs activated the IMD/NFκB immune pathway in the head through remodeling of the commensal gut bacteria. Removal of gut microbiota abolished such HFD-induced remote inflammatory response. Further experiments revealed that HFDs significantly increased the abundance of Acetobacter malorum in the gut, and the re-association of this bacterium was sufficient to elicit inflammatory response in remote tissues. Mechanistically, Acetobacter malorum produced a greater amount of peptidoglycan (PGN), a well-defined microbial molecular pattern that enters the circulation and remotely activates an inflammatory response. Our results thus show that HFDs trigger inflammation mediated by a bacterial molecular pattern that elicits host immune response.

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“…20 Neurons originating in the celiac ganglion and innervating the spleen also release neuropeptide Y that dampen local splenic inflammatory response after LPS (lipopolysaccharide) stimulation and are able to restore immune balance in autoimmune diseases. 21 Although the spleen is not directly innervated by cholinergic fibers, acetylcholine was found in tissue homogenates, and recent work demonstrated that it is locally produced by FRCs 22 and immune cells 23 and is able to modulate lipid metabolism and immune cell differentiation and activation. In particular, it was shown that, upon splenic noradrenergic discharge, a specific subset of CD4 T cells, expressing the enzyme ChAT (choline acetyltransferase), release acetylcholine, which in turn modulates the activity of macrophages.…”

Section: Sensory and Noradrenergic Fibers Innervating The Spleenmentioning

confidence: 99%

Brain-Splenic Immune System Interactions in Hypertension: Cellular and Molecular Mechanisms

Perrotta,

Carnevale

2024

ATVB

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Hypertension represents a major worldwide cause of death and disability, and it is becoming increasingly clear that available therapies are not sufficient to reduce the risk of major cardiovascular events. Various mechanisms contribute to blood pressure increase: neurohormonal activation, autonomic nervous system imbalance, and immune activation. Of note, the brain is an important regulator of blood pressure levels; it recognizes the peripheral perturbation and organizes a reflex response by modulating immune system and hormonal release to attempt at restoring the homeostasis. The connection between the brain and peripheral organs is mediated by the autonomic nervous system, which also modulates immune and inflammatory responses. Interestingly, an increased autonomic nervous system activity has been correlated with an altered immune response in cardiovascular diseases. The spleen is the largest immune organ exerting a potent influence on the cardiovascular system during disease and is characterized by a dense noradrenergic innervation. Taken together, these aspects led to hypothesize a key role of neuroimmune mechanisms in the onset and progression of hypertension. This review discusses how the nervous and splenic immune systems interact and how the mechanisms underlying the neuroimmune cross talk influence the disease progression.

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Neuron-derived neuropeptide Y fine-tunes the splenic immune responses

Cited by 28 publications

References 68 publications

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

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

High-fat diets induce inflammatory IMD/NFκB signaling via gut microbiota remodeling in Drosophila

Brain-Splenic Immune System Interactions in Hypertension: Cellular and Molecular Mechanisms

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