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Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis
Open accessAbstract
The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
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In the citing paper
“Splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation fails to reduce levels further (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“Recent studies of the physiology, functional anatomy, and cellular molecular mechanisms of the cholinergic antiinflammatory pathway indicate that the principal components for cytokine suppression by the vagus nerve converge in the spleen (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“Vagus nerve stimulation in WT mice inhibits TNF synthesis in spleen, liver, and blood but not in α7 nAChR subunit-knockout animals (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“The functional anatomic mechanism of vagus nerve-derived signals to spleen traverses the common celiac branch of the vagus nerve because common celiac branch vagotomy abrogates the TNF-suppressing effects of vagus nerve stimulation in spleen and serum.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“As the vagus nerve does not signal directly to either the paw or the subcutaneous tissues, it is likely that the reduction in inflammation observed following vagus nerve stimulation in these models is attributable to the downregulation of cytokine production by the reticuloendothelial system and redirection of leukocyte trafficking away from the periphery (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
In the citing paper
“And now it appears that a major source of systemic TNF during lethal challenges is the spleen, the source of Galen's black bile (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
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Items 201–300 of 681
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ResultSelf-citationAutonomic balance determines the severity of COVID-19 courses
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A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation
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“The proinflammatory cytokines in circulation are mainly from splenic macrophages in sepsis, and the decreased inflammatory cytokines levels alleviated the organ inflammatory injury and improved the outcome.(44,45) The results further indicated the potential anti-inflammatory and systemic protective effects of GSNO in…”
BackgroundBrain control of appetite during sickness
Aviello, G., Cristiano, C., Luckman, S. M., & D’Agostino, G. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15189 · Cited by 50
“Activated DMV neurons have been proposed to relay this signal to sympathetic ganglia innervating the spleen and to promote noradrenaline release (Huston et al., 2006).”
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Mughrabi, I. T., Hickman, J. L., Jayaprakash, N., Thompson, D., Ahmed, U., Papadoyannis, E. S., Chang, Y.-C., Abbas, A., Datta, T., Chang, E. H., et al. (2021) · eLife · doi:10.7554/elife.61270 · Cited by 52
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“Analogous to virtually all animal and human VNS studies, we stimulated the left vagus nerve to minimize cardiac side effects and to increase outflow to the spleen, which is implicated in mediating the anti-inflammatory effects of VNS [38].”
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“Also, vagus nerve stimulation fails to inhibit TNF α production in splenectomized animals during lethal endotoxemia, demonstrating cholinergic innervation of the spleen (Huston et al., 2006).”
BackgroundVagus nerve stimulation and Neurotrophins: a biological psychiatric perspective
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“Therefore, the pro-inflammatory response in the skin to UVB, like the spleen in animals treated with LPS (Huston et al., 2006), is increased in the absence of α7, however the influence on this response is not dependent upon vagal innervation and the prominent cytokine affected is IL-1β.”
BackgroundA novel regulator of lung inflammation and immunity: pulmonary parasympathetic inflammatory reflex
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“In an endotoxemia mouse model (systemic challenge), activation of a7 nAChR by vagus nerve stimulation reduced the levels of TNF-a in the plasma, liver and spleen, but not in the lung.(4) However, in an acute lung injury model (local challenge), expression of a7 nAChR in alveolar macrophages and neutrophils was increas…”
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“Therefore, the splenic nerve participates in this inflammatory reflex (41).”
BackgroundHuman ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve
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“Splenectomy also inactivates the cholinergic anti-inflammatory pathway, demonstrating the involvement of the RE”
BackgroundVagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19
Azabou, É., Bao, G., Bounab, R., Heming, N., & Annane, D. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.625836 · Cited by 42
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“The α7nAChR is the pivotal receptor in the cholinergic anti-inflammatory pathway and is widely expressed in the CNS (Sharma and Vijayaraghavan, 2001; Gotti and Clementi, 2004; Shytle et al., 2004; Huston et al., 2006; De Jaco et al., 2017).”
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“For example, a key effector organ of the cholinergic anti-inflammatory pathway is the spleen, one of the major cytokine-producing organs (34, 35).”
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“Moreover, this pathway is functionally hardwired to the spleen via the common coeliac branch of the vagus nerve, and the spleen is required for the anti-inflammatory potential of the vagus nerve [11].”
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The Role of the Vagus Nerve: Modulation of the Inflammatory Reaction in Murine Polymicrobial Sepsis
Keßler, W., Diedrich, S., Menges, P., Ebker, T., Nielson, M., Partecke, L. I., Traeger, T., Cziupka, K., van der Linde, J., Puls, R., et al. (2012) · Mediators of Inflammation · doi:10.1155/2012/467620 · Cited by 40
“In particular, the efferent vagus can inhibit inflammation via interaction between acetylcholine and α7 subunit of cholinergic receptors [45].”
BackgroundKooijman, S., Meurs, I., van Beek, L., Khedoe, P. P. S. J., Giezekamp, A., Pike‐Overzet, K., Cailotto, C., van der Vliet, J., van Harmelen, V., Boeckxstaens, G. E., et al. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00787.2014 · Cited by 39
“(11) reported that vagus nerve stimulation fails to inhibit TNFproduction in splenectomized animals during endotoxemia, indicating an essential role for the spleen in the cholinergic anti-inflammatory pathway.”
BackgroundIslas-Weinstein, L., Revuelta, A., & Hernández‐Pando, R. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12792 · Cited by 38
Neuroimmune Interactions in Inflammation and Acute Kidney Injury
Inoue, T., Tanaka, S., & Okusa, M. D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00945 · Cited by 39
“revealed that the spleen is the major source of TNF-α after LPS challenge, and VNS-induced inhibition of systemic TNF-α production was abolished in splenectomized animals (22).”
BackgroundVagal nerve stimulation modulates gut injury and lung permeability in trauma-hemorrhagic shock
Levy, G., Fishman, J. E., Xu, D.-Z., Dong, W., Palange, D., Vida, G., Mohr, A. M., Ulloa, L., & Deitch, E. A. (2012) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e31825debd3 · Cited by 38
“Vagal Nerve Stimulation The vagus nervewas stimulated as previously described.(10) Briefly, once all cannulas were in place, the left side of the animal’s neck was subjected to dissection, and the carotid artery was identified.”
MethodSelf-citationModulation of host immunity by sensory neurons
Saraiva‐Santos, T., Zaninelli, T. H., & Pinho-Ribeiro, F. A. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.03.005 · Cited by 36
The interface between cholinergic pathways and the immune system and its relevance to arthritis
McAllen, R. M., Cook, A. D., Khiew, H. W., Martelli, D., & Hamilton, J. A. (2015) · Arthritis Research & Therapy · doi:10.1186/s13075-015-0597-2 · Cited by 38
“It involves the spleen [20] and the splenic nerves [14], but the proposal [15] that it is mediated by a direct synaptic connection from the vagus to the splenic nerves (which are sympathetic) has been refuted [21].”
BackgroundKong, S.-S., Liu, J.-J., Hwang, T., Yu, X.-J., Zhao, M., Zhao, M., Yuan, B.-X., Lü, Y., Kang, Y.-M., Wang, B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042799 · Cited by 37
“This observation was also confirmed repeatedly by others [12,13,14].”
ResultLi‐Sha, G., Chen, X.-X., Wu, L., Zhou, D., Li, X., Lin, J., & Li, Y. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00025 · Cited by 37
Chronic cuffing of cervical vagus nerve inhibits efferent fiber integrity in rat model
Somann, J. P., Albors, G. O., Neihouser, K. V., Lu, K.-H., Liu, Z.-M., Ward, M. P., Durkes, A., Robinson, J. P., Powley, T., & Irazoqui, P. (2017) · Journal of Neural Engineering · doi:10.1088/1741-2552/aaa039 · Cited by 34
The Pathophysiology of Septic Shock
Nduka, O. O., & Parrillo, J. E. (2011) · Critical Care Nursing Clinics of North America · doi:10.1016/j.ccell.2010.12.003 · Cited by 38
“In addition, rendering these animals immune to vagal stimulation either by genetic manipulation or vagotomy led to an exaggerated proinflammatory cytokine response.(51) It is now understood that these cytokine-suppressive effects of vagal stimulation are mediated by the release of its neurotransmitter acetylcholine (A…”
Deficiency of α7 Cholinergic Receptors Facilitates Bacterial Clearance inEscherichia coliPeritonitis
Giebelen, I. A. J., Moine, A. L., van den Pangaart, P. S., Sadis, C., Goldman, M., Florquin, S., & van der Poll, T. (2008) · The Journal of Infectious Diseases · doi:10.1086/590432 · Cited by 36
Management of post-splenectomy patients in the Netherlands
Lammers, A. J. J., Veninga, D., Lombarts, K. M. J. M. H., Hoekstra, J. B. L., & Speelman, P. (2010) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-009-0870-x · Cited by 36
“After splenectomy, there is a diminished clearance of poorly opsonised bacterial antigens, an impaired primary humoral response to antigenic challenge and loss of the vagally mediated anti-inflammatory cholinergic response [3, 4].”
BackgroundGrech, D., Li, Z., Morcillo, P., Kalyoussef, E., Kim, D. D., Bekker, A., & Ulloa, L. (2016) · Journal of Acupuncture and Meridian Studies · doi:10.1016/j.jams.2016.03.009 · Cited by 36
Self-citationRole of neurons in the control of immune defense
Hoffman, C. L., & Aballay, A. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.04.005 · Cited by 36
Jarczyk, J., Yard, B. A., & Hoeger, S. (2019) · Kidney & Blood Pressure Research · doi:10.1159/000500920 · Cited by 36
The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galantamine
Gowayed, M. A., Rothe, K., Rossol, M., Attia, A. S., Wagner, U. G., Baerwald, C., El-Abhar, H. S., & Refaat, R. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.113665 · Cited by 36
Fernández-Cabezudo, M. J., Lorke, D. E., Azimullah, S., Mechkarska, M., Hasan, M. Y., Petroianu, G. A., & al-Ramadi, B. K. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03238.x · Cited by 36
Modulation of the Innate Immune Response through the Vagus Nerve
Kox, M., & Pickkers, P. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000435843 · Cited by 35
Morishita, K., Coimbra, R. S. M., Langness, S. M., Eliceiri, B. P., & Costantini, T. W. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00097.2015 · Cited by 35
Seeley, E. J., Barry, S. S., Narala, S., Matthay, M. A., & Wolters, P. J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300027 · Cited by 36
“These studies show that signals originating from the vagus nerve synapse at the celiac mesenteric ganglion and then travel to the spleen via the splenic nerve where acetylcholine-producing T cells act as intermediaries between splenic nerve-derived NE and a7 acetylcholine receptor–bearing macrophages (18, 19).”
BackgroundSomann, J. P., Wasilczuk, K. M., Neihouser, K. V., Sturgis, J. E., Albors, G. O., Robinson, J. P., Powley, T., & Irazoqui, P. (2019) · PLoS ONE · doi:10.1371/journal.pone.0214317 · Cited by 34
Huston, J. M., Ochani, M., Rosas‐Ballina, M., Liao, H., Ochani, K., Pavlov, V. A., Gallowitsch‐Puerta, M., Ashok, M., Czura, C. J., Foxwell, B. M. J., et al. (2006) · The Journal of Cell Biology · doi:10.1083/jcb1741oia1 · Cited by 35
Self-citationVagal sensory pathway for the gut-brain communication
Cao, Y., Li, R., & Bai, L. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.07.009 · Cited by 38
Dong, W., Cai, B., Peña, G., Pisarenko, V., Vida, G., Doucet, D. R., Lee, M., Sharpe, S., Lu, Q., Xu, D.-Z., et al. (2010) · Shock · doi:10.1097/shk.0b013e3181cc0c63 · Cited by 34
“splenectomy attenuated serum TNF levels in experimental sepsis (35).”
BackgroundSelf-citationThe clinical importance of the anti-inflammatory vagovagal reflex
Boeckxstaens, G. E. (2013) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53491-0.00011-0 · Cited by 34
“…IMPORTANCE OF THE AN The efferent limb of the inflammatory reflex As the spleen is the major source of TNF and HMGB1, two key cytokines in the pathophysiology of sepsis (Huston et al., 2006, 2008; Qin et al., 2006), it represents an ideal target for neural modulation of the immune response.”
Background2 Vagal control of gastrointestinal function
Grundy, D. (1988) · Baillière s Clinical Gastroenterology · doi:10.1016/0950-3528(88)90019-x · Cited by 34
Impact of broad-spectrum antibiotics on the gut–microbiota–spleen–brain axis
Wan, X., Eguchi, A., Sakamoto, A., Fujita, Y., Yang, Y. H., Qu, Y., Hatano, M., Mori, C., & Hashimoto, K. (2022) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2022.100573 · Cited by 34
Phytochemicals derived from Nicotiana tabacum L. plant contribute to pharmaceutical development
Zhang, W., Pan, X., Fu, J., Cheng, W., Lin, H., Zhang, W., & Huang, Z. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1372456 · Cited by 40
Neuroimmune modulation in liver pathophysiology
Zou, J., Li, J., Wang, X., Tang, D., & Chen, R. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03181-w · Cited by 36
“The splenic nerve plays an essential role in mediating the anti-inflammatory effects of VNS in LPS-induced endotoxemia [245, 246].”
BackgroundVagal influences in rheumatoid arthritis
Rasmussen, S. E., Pfeiffer‐Jensen, M., Drewes, A. M., Farmer, A. D., Deleuran, B. W., Stengaard‐Pedersen, K., Brock, B., & Brock, C. (2017) · Scandinavian Journal of Rheumatology · doi:10.1080/03009742.2017.1314001 · Cited by 33
“The first and original model of the inflammatory reflex has been referred to as both the ‘inflammatory reflex’ and the CAP (15, 56), whereas the latter is often used to describe the efferent pathway of the reflex (50).”
BackgroundInfluentialUni, R., Inoue, T., Nakamura, Y., Fukaya, D., Hasegawa, S., Wu, C.-H., Fujii, R., Surattichaiyakul, B., Peerapanyasut, W., Ozeki, A. N., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-66295-0 · Cited by 33
Transdermal auricular vagus stimulation for the treatment of postural tachycardia syndrome
Diedrich, A., Urechie, V., Shiffer, D., Rigo, S., Minonzio, M., Cairo, B., Smith, E. C., Okamoto, L. E., Barbic, F., Bisoglio, A., et al. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102886 · Cited by 36
Cholinergic dysfunction in COVID-19: frantic search and hoping for the best
Nadwa, E. H., Al-Kuraishy, H. M., Al-Gareeb, A. I., Elekhnawy, E., Albogami, S. M., Alorabi, M., Batiha, G. E., & WAARD, M. M. D. (2022) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-022-02346-9 · Cited by 33
Sun, Z., Xiang, Y.-X., Wang, W.-X., Xue, Z., Zhu, L., & Wang, S.-B. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.155430 · Cited by 33
“Numerous studies have shown that electrical stimulation of the vagus nerve can reduce the production of TNF-α and other cytokines in experimental models of endotoxemia and hemorrhagic shock (Bernik et al., 2002; Guarini et al., 2003; Wang et al., 2003; Huston et al., 2006).”
BackgroundThe cholinergic anti-inflammatory pathway meets microRNA
Ulloa, L. (2013) · Cell Research · doi:10.1038/cr.2013.128 · Cited by 33
Self-citationLeite, H. R., Oliveira‐Lima, O. C., Pereira, L. D. M., Oliveira, V. E. D. M., Prado, V. F., Prado, M. A. M., Pereira, G. S., & Massensini, A. R. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.05.005 · Cited by 35
Griton, M., & Konsman, J. P. (2018) · Clinical Autonomic Research · doi:10.1007/s10286-018-0518-y · Cited by 33
Shelukhina, I. V., Siniavin, A. E., Kasheverov, I. E., Ojomoko, L. O., Tsetlin, V. I., & Utkin, Y. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076524 · Cited by 33
Glucose Activates Vagal Control of Hyperglycemia and Inflammation in Fasted Mice
Joseph, B., Shimojo, G. L., Li, Z., Thompson-Bonilla, M. D. R., Shah, R., Kanashiro, A., Salgado, H. C., & Ulloa, L. (2019) · Scientific Reports · doi:10.1038/s41598-018-36298-z · Cited by 30
Self-citationCholinergic signalling in gut immunity
Dhawan, S., Cailotto, C., Harthoorn, L. F., & de Jonge, W. J. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.04.042 · Cited by 31
Metadata
- Authors
- Huston, J. M., Ochani, M., Rosas-Ballina, M., Liao, H., Ochani, K., Pavlov, V. A., Gallowitsch-Puerta, M., Ashok, M., Czura, C. J., Foxwell, B., Tracey, K. J., & Ulloa, L.
- Affiliations
- 1Laboratory of Biomedical Science
- Imperial College London (GB)
- Northwell Health (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-06-19
- Volume
- 203
- Issue
- 7
- Pages
- 1623-1628
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118357
- OpenAlex
- W2154170498
- Cited by
- 683
- References
- 30
- Citations by year
- 2026: 25 · 2025: 22 · 2024: 37 · 2023: 32 · 2022: 50 · 2021: 51 · 2020: 37 · 2019: 44 · 2018: 33 · 2017: 40 · 2016: 29 · 2015: 31 · 2014: 36 · 2013: 25 · 2012: 39
- FWCI
- 18.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- National Institute of General Medical Sciences (R01GM057226)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- splenectomy, cholinergic anti-inflammatory pathway, vagus nerve stimulation, alpha7 nicotinic acetylcholine receptor, endotoxemia, polymicrobial sepsis, TNF-α, reticuloendothelial system, spleen, nicotine, inflammatory cytokines, neuroimmune regulation
- MeSH terms
- Acetylcholine, Animals, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Rats, Inbred Lew, Splenectomy, Signal Transduction, Mice, Knockout, Sepsis, Endotoxemia, Mice, Rats
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