Nicotine, Inflammation and the Immune System

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1. The Papers
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The Papers (17)

Newest first. Study types on this page — Animal study: 12 · Cell study: 2 · Chemistry / laboratory method: 1 · Other: 2. Each summary is written from the paper’s own abstract; follow the PubMed link for the full record.

An inhibitory brainstem input to dopamine neurons encodes nicotine aversion

Animal study, 2022. This study in mice looked at why nicotine is rewarding at lower doses but unpleasant at high doses. High doses that caused avoidance behavior in mice first quieted and then excited the brain's dopamine cells, with the two effects reaching different parts of a reward area called the nucleus accumbens. The quieting effect involved two types of nicotinic receptors, alpha4beta2 and alpha7, and depended on a group of inhibitory nerve cells in a brainstem region called the laterodorsal tegmentum. When the researchers blocked the signal from these brainstem cells, the mice no longer avoided high-dose nicotine; these results are only in mice.

Liu C, Tose AJ, Verharen JPH et al. (2022). An inhibitory brainstem input to dopamine neurons encodes nicotine aversion. Neuron. — PubMed PMID: 35921846 · doi:10.1016/j.neuron.2022.07.003

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

Animal study, 2020. Researchers studied how nicotine affects salt and fluid movement across the lining of the windpipe. This movement helps the airways clear mucus and germs. The work used windpipes and windpipe-lining cells taken from mice. When nicotine was applied to the inner surface, it caused a brief rise in ion transport. This effect needed nicotinic receptors containing a β4 subunit, mainly the α3β4 type: it vanished in mice lacking β4 but stayed normal in mice lacking β2. The effect worked through calcium released from stores inside the cells, an enzyme called PKA, and a calcium-activated chloride channel called TMEM16A. The authors suggest these receptors might be possible targets for boosting chloride transport, but the findings come only from mouse tissue.

Kumar P, Scholze P, Fronius M et al. (2020). Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors. Br J Pharmacol. — PubMed PMID: 32959891 · doi:10.1111/bph.15270

Nicotine Rescues Depressive-like Behaviors via α7-type Nicotinic Acetylcholine Receptor Activation in CaMKIV Null Mice

Animal study, 2020. This study was done only in mice bred to lack a brain enzyme called CaMKIV, which makes them show depression-like behavior. Giving the mice nicotine at 0.03-0.3 mg/kg for 14 days reversed that depression-like behavior and raised activity in brain pathways tied to the growth of new nerve cells, including higher levels of a nerve growth factor called BDNF in the hippocampus. The benefit disappeared when one type of nicotine receptor, the alpha-7 type, was blocked, and drugs that activate only that receptor gave a similar benefit. The authors conclude that in these mice nicotine's effect on depression-like behavior works through the alpha-7 nicotinic receptor.

Moriguchi S, Inagaki R, Yi L et al. (2020). Nicotine Rescues Depressive-like Behaviors via α7-type Nicotinic Acetylcholine Receptor Activation in CaMKIV Null Mice. Mol Neurobiol. — PubMed PMID: 32815115 · doi:10.1007/s12035-020-02077-z

COVID-19 and the nicotinic cholinergic system

Other, 2020. This short letter discusses COVID-19 and the body's nicotinic cholinergic system, the network of receptors that nicotine acts on. The authors note that smoking appears to be uncommon among people hospitalised with COVID-19. They propose that some COVID-19 symptoms could be linked to a breakdown of the cholinergic anti-inflammatory pathway, a nerve-based system that helps calm inflammation. They suggest that substances that activate nicotinic receptors should be studied as possible treatments; the letter reports no new experiments or patient data.

Farsalinos K, Angelopoulou A, Alexandris N et al. (2020). COVID-19 and the nicotinic cholinergic system. Eur Respir J. — PubMed PMID: 32444400 · doi:10.1183/13993003.01589-2020

COVID-19 and nicotine as a mediator of ACE-2

Other, 2020. This is a short letter to a lung medicine journal, written early in the COVID-19 pandemic, about how nicotine might be connected to ACE-2. ACE-2 is the protein on the surface of cells that the COVID-19 virus uses to get in. The letter suggests that the alpha-7 nicotinic receptor, which nicotine acts on, may increase the amount of ACE-2 on cells. This is an idea put forward for discussion. The abstract reports no experiment, no participants and no measured results.

Leung JM, Yang CX, Sin DD (2020). COVID-19 and nicotine as a mediator of ACE-2. Eur Respir J. — PubMed PMID: 32350104 · doi:10.1183/13993003.01261-2020

MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1

Animal study, 2020. Smoking seems to ease ulcerative colitis but worsen Crohn's disease, two forms of inflammatory bowel disease that are driven by different types of immune response (Th2 and Th1). Researchers studied mice with chemically induced colitis that resembles ulcerative colitis, plus human white blood cells in the lab. They found that nicotine pushes the immune balance toward the Th1 type by raising a small regulatory molecule called microRNA-124, which acts through the IL-6 receptor. When microRNA-124 was blocked, nicotine no longer caused this shift, and the mouse colitis got worse. The authors suggest this may explain why nicotine could help one form of inflammatory bowel disease but harm the other, though the findings come only from mice and cells.

Qin Z, Wang PY, Wan JJ et al. (2020). MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1. Front Immunol. — PubMed PMID: 32153570 · doi:10.3389/fimmu.2020.00235

A Small Library of 1,2,3-Triazole Analogs of CAP-55: Synthesis and Binding Affinity at Nicotinic Acetylcholine Receptors

Chemistry / laboratory method, 2018. Chemists started from a nicotine-derived compound called CAP55, which earlier work showed calms inflammation by acting on nicotinic receptors. They made a small set of related compounds by replacing one ring in its structure with a different ring. In laboratory binding tests on nicotinic acetylcholine receptors, two of the new compounds (numbers 4 and 10) looked promising and were judged worth further study. This was chemistry and receptor-binding work only, with no tests in animals or people.

Rizzi L, Gotti C, De Amici M et al. (2018). A Small Library of 1,2,3-Triazole Analogs of CAP-55: Synthesis and Binding Affinity at Nicotinic Acetylcholine Receptors. Chem Biodivers. — PubMed PMID: 29953725 · doi:10.1002/cbdv.201800210

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

Animal study, 2018. This laboratory study looked at the alpha-7 nicotinic receptor, one of the brain receptors nicotine acts on. It used hippocampal brain tissue, which handles memory, and frog egg cells engineered to carry the receptors. In these experiments, nicotine added to the brain tissue did not significantly strengthen the connections between nerve cells, even though earlier work had reported that it did. A test compound called NS6740, which binds to the alpha-7 receptor but barely opens its channel, weakened both normal signalling between nerve cells and the strengthening of those connections; it shut off the alpha-7 receptor's response to the body's own messenger acetylcholine but did not affect the other receptors tested. All results come from animal tissue and cells, not from people.

Papke RL, Peng C, Kumar A et al. (2018). NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity. Neurosci Lett. — PubMed PMID: 29679680 · doi:10.1016/j.neulet.2018.04.025

Isobaric Tag-Based Protein Profiling of a Nicotine-Treated Alpha7 Nicotinic Receptor-Null Human Haploid Cell Line

Cell study, 2018. Researchers studied how nicotine changes the proteins in two lines of lab-grown human cells. One line was normal and the other lacked the alpha7 nicotinic receptor, a protein on the cell surface that nicotine binds to. They measured 8775 proteins, and several hundred changed in amount, both between the two cell lines and after nicotine treatment. Nicotine raised the levels of proteins called APP, APLP2 and ITM2B, and these rises were larger in the normal cells, which suggests the alpha7 receptor plays a part. Most of the proteins that changed were membrane proteins or proteins usually linked to nerve cells. These results come from cells grown in the lab, not from people or animals.

Paulo JA, Gygi SP (2018). Isobaric Tag-Based Protein Profiling of a Nicotine-Treated Alpha7 Nicotinic Receptor-Null Human Haploid Cell Line. Proteomics. — PubMed PMID: 29663646 · doi:10.1002/pmic.201700475

The alpha-7 nicotinic acetylcholine receptor is involved in a direct inhibitory effect of nicotine on GnRH release: In vitro studies

Cell study, 2018. This laboratory study used a line of mouse brain cells that make GnRH, the hormone that starts the body's reproductive signalling, to see whether nicotine acts on these cells directly. The cells had nicotinic receptors of two types (alpha4beta2 and alpha7). Nicotine did not change the cells' resting GnRH levels, but it changed the rhythm of GnRH release and reduced the release normally triggered by other stimuli; blocking the receptors reversed these effects, and the alpha7 type appeared to carry the reducing effect. The results come from cells only, and the authors suggest this direct action of nicotine on GnRH cells may help explain the lower fertility seen in smokers.

Messi E, Pimpinelli F, Andrè V et al. (2018). The alpha-7 nicotinic acetylcholine receptor is involved in a direct inhibitory effect of nicotine on GnRH release: In vitro studies. Mol Cell Endocrinol. — PubMed PMID: 28754351 · doi:10.1016/j.mce.2017.07.025

Nicotinic modulation of descending pain control circuitry

Animal study, 2017. Researchers studied nicotinic receptors, the brain receptors that nicotine acts on, in a pain-control pathway running from the midbrain to the brainstem. They used brain slices from adult male rats and found that 63% of the nerve cells in this pathway had working nicotinic receptors, all of the alpha-7 type, and these were mostly different cells from the ones carrying opioid receptors. In rats, a lab drug that switches on only alpha-7 receptors reduced pain responses in a formalin pain test, whether it was given by injection into the body or directly into this brain area. Blocking alpha-7 receptors in that brain area stopped the effect, and lower doses of the drug combined with morphine added together to reduce pain. These results come from rats only.

Umana IC, Daniele CA, Miller BA et al. (2017). Nicotinic modulation of descending pain control circuitry. Pain. — PubMed PMID: 28817416 · doi:10.1097/j.pain.0000000000000993

Serotonergic modulation of nicotine-induced kinetic tremor in mice

Animal study, 2017. This study in mice looked at how the brain chemical serotonin affects the shaking (a tremor that appears during movement) that nicotine causes. The researchers had already shown that nicotine triggers this tremor by acting on α7 nicotinic receptors in a brainstem area called the inferior olive. In this study, a drug that activates serotonin 5-HT1A receptors made the nicotine tremor stronger, and blocking those receptors reduced it, while a drug that activates 5-HT2 receptors weakened the tremor. The authors conclude that 5-HT1A receptors help produce nicotine-induced tremor and 5-HT2 receptors hold it back, but these results come only from mice.

Kunisawa N, Iha HA, Nomura Y et al. (2017). Serotonergic modulation of nicotine-induced kinetic tremor in mice. J Pharmacol Sci. — PubMed PMID: 28647281 · doi:10.1016/j.jphs.2017.06.001

Nicotine stimulates collagen type I expression in lung via α7 nicotinic acetylcholine receptors

Animal study, 2017. Researchers exposed lung connective-tissue cells (fibroblasts) from normal mice and from mice lacking the alpha-7 nicotinic receptor to nicotine, and also gave female mice nicotine in their drinking water for 8 to 12 weeks. Nicotine increased the cells' production of collagen type I and made them multiply, but not in cells or mice lacking the alpha-7 receptor. Normal mice given nicotine had more collagen in the lung, mostly around the airways, but the overall structure of the lung did not change. In lab tests, immune cells grown on the collagen-rich material made by nicotine-treated cells produced more of the inflammatory signal IL-1β; the authors suggest this could affect inflammation after lung injury. These results are from cells and mice only, not people.

Vicary GW, Ritzenthaler JD, Panchabhai TS et al. (2017). Nicotine stimulates collagen type I expression in lung via α7 nicotinic acetylcholine receptors. Respir Res. — PubMed PMID: 28576119 · doi:10.1186/s12931-017-0596-8

Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis

Animal study, 2017. Researchers looked at neutrophil extracellular traps (NETs), which are web-like strands of DNA that a type of white blood cell called a neutrophil throws out. They studied this in blood cells from smokers and non-smokers, and in mice with a lab model of rheumatoid arthritis. Neutrophils from smokers formed more NETs. When nicotine was added in the lab to neutrophils from healthy non-smokers, they formed more NETs as the dose went up, and this worked through the alpha-7 nicotinic receptor on those cells. In the mice, nicotine made the arthritis worse and raised blood markers of NETs, so the authors suggest that nicotine-containing products, including e-cigarettes, may be harmful for people with rheumatoid arthritis.

Lee J, Luria A, Rhodes C et al. (2017). Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology (Oxford). — PubMed PMID: 28013195 · doi:10.1093/rheumatology/kew449

Chronic nicotine treatment decreases LPS signaling through NF-κB and TLR-4 modulation in the hippocampus

Animal study, 2017. This study looked at whether giving nicotine daily for 14 days changes inflammation in the hippocampus, a memory area of the brain that has many nicotinic receptors, especially the alpha-7 type. The animals were then exposed to LPS, a piece of bacteria that triggers inflammation. In the animals given nicotine, LPS switched on less of NF-kB, an inflammation 'master switch', and less of the inflammation genes Tnf, Il1b, Nos2 and Tlr4. Drugs that block nicotinic receptors, including one that blocks only the alpha-7 type, cancelled this effect, which suggests nicotine acts through these receptors; the result comes from animals only, not from people.

Café-Mendes CC, Garay-Malpartida HM, Malta MB et al. (2017). Chronic nicotine treatment decreases LPS signaling through NF-κB and TLR-4 modulation in the hippocampus. Neurosci Lett. — PubMed PMID: 27984197 · doi:10.1016/j.neulet.2016.10.056

Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells

Animal study, 2017. This study looked at whether nicotine speeds up the buildup of fatty plaques in arteries (atherosclerosis), using mice bred to develop the disease and fed a high-fat diet. Mice given nicotine developed larger plaques, with more inflammatory cells and fat in them and less of the collagen and muscle cells that help keep plaques stable. Mice that lacked mast cells (a type of immune cell) had much less of this nicotine effect. The researchers found that nicotine works by switching on a specific nicotine receptor, the alpha-7 nicotinic receptor, on mast cells; these results come only from mice and cells grown in the lab.

Wang C, Chen H, Zhu W et al. (2017). Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells. Arterioscler Thromb Vasc Biol. — PubMed PMID: 27834689 · doi:10.1161/ATVBAHA.116.307264

Activation of the cholinergic antiinflammatory pathway reduces ricin-induced mortality and organ failure in mice

Animal study, 2009. This study tested whether nicotine could protect male mice poisoned with ricin, a toxin from castor oil plant seeds. Ricin raised blood levels of an inflammatory signal called tumor necrosis factor-alpha, damaged the kidneys and liver, and killed many of the mice. Mice given nicotine 2 hours after the ricin died later and less often, and they had less inflammation, less kidney and liver damage, and less oxidative stress in those organs. The authors suggest that nicotine works by switching on a nerve-based anti-inflammatory pathway through the alpha7 nicotinic receptor, but these results come only from mice.

Mabley JG, Pacher P, Szabo C (2009). Activation of the cholinergic antiinflammatory pathway reduces ricin-induced mortality and organ failure in mice. Mol Med. — PubMed PMID: 19209239 · doi:10.2119/molmed.2008.00105

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1. PubMed: Inflammation and Immunity and nicotine (the search this page is built from)

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Connections

• Nicotine: The Research
• The Nicotine Patch, animated
• Nicotinic Acetylcholine Receptors
• Cigarette Smoke — what burnt tobacco adds that nicotine alone does not
• Brain and Memory
• Mood and Mental Health
• Cancer Research
• Heart and Blood Vessels
• Metabolism and Weight
• Addiction and Withdrawal
• Patches, Gum and Delivery
• Toxicity and Safety

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