Cholinergic Regulatory Lymphocytes Re-Establish Neuromodulation of Innate Immune Responses in Sepsis

Peña, Geber; Cai, Bolin; Ramos, Laura; Vida, Gergely; Deitch, Edwin A.; Ulloa, Luis

doi:10.4049/jimmunol.1100013

Cited by 51 publications

(55 citation statements)

References 69 publications

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“…In addition, experiments performed by our group confirmed these results [36,38,44]. Other beneficial effects from electrical vagal stimulation in endotoxemic animals include attenuation of the coagulant and fibrinolytic systems [45] and of disruption of tight junction in the intestinal epithelium [46].…”

Section: The Inflammatory Reflexmentioning

confidence: 63%

Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis

Kanashiro

Sônego

Ferreira

et al. 2017

Pharmacological Research

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Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called “cholinergic anti-inflammatory pathway”, suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.

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Section: The Inflammatory Reflexmentioning

confidence: 63%

Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis

Kanashiro

Sônego

Ferreira

et al. 2017

Pharmacological Research

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“…In contrast to the earlier hypotheses proposing a direct effect of ACh released by vagal efferents,2 recent evidence suggests that the vagus indirectly interacts with the spleen through adrenergic neurons located in the coeliac mesenteric ganglia, leading to the release of norepinephrine via the splenic nerve 6. Recently, memory T cells (in a β2-adrenoceptor-dependent fashion rather than vagal efferents), were proposed as a final source of ACh in the spleen, driving lower cytokine production by splenic macrophages 7 36 37. Clearly, as the spleen plays a central role in sepsis, this organ should be the main target of immune modulation.…”

Section: Discussionmentioning

confidence: 99%

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

Matteoli

Gomez‐Pinilla

Némethova

et al. 2013

Gut

345

340

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The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagus nerve stimulation (VNS) reduces intestinal inflammation and improves postoperative ileus. We investigated the neural pathway involved and the cells mediating the anti-inflammatory effect of VNS in the gut. The effect of VNS on intestinal inflammation and transit was investigated in wild-type, splenic denervated and Rag-1 knockout mice. To define the possible role of α7 nicotinic acetylcholine receptor (α7nAChR), we used knockout and bone marrow chimaera mice. Anterograde tracing of vagal efferents, cell sorting and Ca(2+) imaging were used to reveal the intestinal cells targeted by the vagus nerve. VNS attenuates surgery-induced intestinal inflammation and improves postoperative intestinal transit in wild-type, splenic denervated and T-cell-deficient mice. In contrast, VNS is ineffective in α7nAChR knockout mice and α7nAChR-deficient bone marrow chimaera mice. Anterograde labelling fails to detect vagal efferents contacting resident macrophages, but shows close contacts between cholinergic myenteric neurons and resident macrophages expressing α7nAChR. Finally, α7nAChR activation modulates ATP-induced Ca(2+) response in small intestine resident macrophages. We show that the anti-inflammatory effect of the VNS in the intestine is independent of the spleen and T cells. Instead, the vagus nerve interacts with cholinergic myenteric neurons in close contact with the muscularis macrophages. Our data suggest that intestinal muscularis resident macrophages expressing α7nAChR are most likely the ultimate target of the gastrointestinal CAIP.

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“…In fact, several other investigators had already established that ChAT mRNA, protein, and activity are upregulated when T cells are activated (Fujii et al, 1998; Fujii et al, 2008; Fujii et al, 2012b; Kawashima and Fujii, 2008). Subsequent studies by Ulloa and coworkers provided strong support for a T cell link between noradrenergic nerves and splenic macrophages, but their data implicated a different subgroup of helper T cells (Peña et al, 2011; Vida et al, 2011b). They also showed that β 2 -adrenergic receptors on these T cells are essential for the anti-inflammatory effects of VNS.…”

Section: Vagal Anti-inflammatory Reflexmentioning

confidence: 99%

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

227

169

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The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

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Cholinergic Regulatory Lymphocytes Re-Establish Neuromodulation of Innate Immune Responses in Sepsis

Cited by 51 publications

References 69 publications

Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis

Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

Cholinergic modulation of the immune system presents new approaches for treating inflammation

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