Nicotine is an Immunosuppressant: Implications for Women's Health and Disease

Abstract

A plethora of evidence supports that nicotine, the primary alkaloid in tobacco products that is generally accepted for maintaining use, is immunoregulatory and may function as an immunosuppressant. Women have unique experiences with use of nicotine-containing products and also undergo significant reproductive transitions throughout their lifespan which may be impacted by nicotine use. Within the extant literature, there is conflicting evidence that nicotine may confer beneficial health effects in specific disease states (e.g., in ulcerative colitis). Use prevalence of nicotine-containing products is exceptionally high in individuals presenting with some comorbid disease states that impact immune system health and can be a risk factor for the development of diseases which disproportionately impact women; however, the mechanisms underlying these relationships are largely unclear. Further, little is known regarding the impacts of nicotine's immunosuppressive effects on women's health during the menopausal transition, which is arguably an inflammatory event characterized by a pro-inflammatory peri-menopause period. Given that post-menopausal women are at a higher risk than men for the development of neurodegenerative diseases such as Alzheimer's disease and are also more vulnerable to negative health effects associated with diseases such as HIV-1 infection, it is important to understand how use of nicotine-containing products may impact the immune milieu in women. In this review, we define instances in which nicotine use confers immunosuppressive, anti-inflammatory, or pro-inflammatory effects in the context of comorbid disease states, and focus on how nicotine impacts neuroimmune signaling to maintain use. We posit that regardless of potential health benefits, nicotine use cessation should be a priority in the clinical care of women. The synthesis of this review demonstrates the importance of systematically defining the relationships between volitional nicotine use, immune system function, and comorbid disease states in women to better understand how nicotine impacts women's health and disease.

Keywords: Addiction; Disease; Immunosuppression; Nicotine; women's health.

Fig. 1.. Dysregulations in the Nucleus Accumbens Pentapartite Synapse After Chronic Nicotine Use.

(A) Under homeostatic conditions, normal glutamate signaling from glutamatergic afferents including from the prelimbic (PL) cortex to GABAergic nucleus accumbens core (NAcore) medium spiny neurons (MSNs) is regulated by surveilling microglia, which are able to orient and respond to neuronal signals. Astrocytic end feet ensheathe synapses and glutamate transporter-1 (GLT-1) expression is located at the synapse to remove the majority of extracellular glutamate from the synapse. Cytokines (including tumor necrosis factor alpha, or TNF-α) are a primary way in which neurons, microglia, and astrocytes communicate and they regulate transcription of various glutamate proteins including GLT-1. Metabotropic glutamate receptor 2/3 (mGluR2/3) function as auto receptors to regulate glutamate release on the presynaptic terminals. (B) Following chronic nicotine use, nicotine binds to nicotinic acetylcholine receptors (nAChRs) located on presynaptic glutamate terminals and on microglia. Enhanced glutamate release occurs, leading to overflow of glutamate into the extra synaptic space. Astrocytic end feet retract from synapses, and GLT-1 is downregulated leading to potential excitotoxicity. Neurons send a “help me” signal to microglia via cleavage of membrane-associated fractalkine (mFKN) into the soluble isoform (sFKN), resulting in binding of sFKN to CX3CR1 receptors located on microglia. Activation of CX3CR1 results in release of adenosine and its subsequent activation of adenosine 2 A receptors (A2ARs), which activate the nuclear factor-kappa B (NF-ĸB) pathway and potentially leads to upregulation of GLT-1 during nicotine seeking under withdrawal conditions. Due to nicotine’s immunosuppressive effects, microglia are unable to respond to this signal, and are stuck in a homeostatic state whereby they cannot orient towards neurons or release cytokines. Under withdrawal conditions in which nicotine is not on board, TNF-α is cleaved and secreted from microglia where it then binds to TNFR on astrocytes, activating the NF-ĸB pathway and leading to suppression of GLT-1 and cytokine gene transcription. ECM = extracellular matrix. Figure was created using BioRender.