Non-Neuronal Acetylcholine: The Missing Link Between Sepsis, Cancer, and Delirium?

Abstract

The interaction between living organisms and the environment requires a balancing act between genomic and epigenomic forces. Inflammation and cellular proliferation are kept in check by the genes, which code for their components and the microRNAs, which are capable of silencing the transcription of these genes. Acetylcholine (ACh) may play a unique role in the maintenance of this equilibrium, as the epigenomic inhibition of the gene coding for nicotinic receptors, and disinhibits the gene causing anergia in immune cells. We hypothesize that age-induced ACh deficiency is the result of an epigenomic dysfunction of microRNA-6775 (miR-6775), which silences the transcription of CHRNA7 gene [coding for alpha 7 nicotinic cholinergic receptors (nAChRs)]. When silenced, this gene induces decreased expression of alpha 7 nAChRs, which may predispose elderly individuals to inflammation, neuroinflammation, and delirium. We hypothesize further that miR-6775-induced hypocholinergia augments the expression of RNF 128, the gene related to anergy in lymphocytes (GRAIL). This gene favors regulatory T cells (Tregs), promoters of immunologic tolerance, which may predispose to both cancer and sepsis-induced immunosuppression.

Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain

“…Naturally expressed α7 nAChRs might mediate classic excitatory neurotransmission at some loci, but they may also modulate the release of other neurotransmitters, neurite outgrowth, and even neuronal survival/death [8,9]. In addition, α7 nAChRs express not only on neurons but also on various types of non-neuronal cells including astrocytes and microglia [10,11] (Box 1). The α7 nAChR, as a target of nicotine action, also has been implicated in the development, differentiation, and pathophysiology of the nervous system [12,13].…”

“…For example, emerging evidence demonstrates that α7 nAChRs are expressed in immune cells including macrophages/monocytes [56], dendritic cells [57], microglia [58] and astrocytes [10,11]. When the α7 nAChRs are activated, nicotine exhibits significant modulations in the production of proinflammatory cytokines, such as interleukin (IL)-1, TNF-α, and IL-1β [59].…”

Proteomic and epigenomic markers of sepsis-induced delirium (SID)

“…The discovery of CNS lymphatics suddenly changed the perspective on the peripheral-central immune cooperation into a holistic one in which astrocytes, microglia and peripheral macrophages work in an innate immune continuum (Sternberg, 2006 ; Louveau et al, 2015 ). For example, the peripheral dendritic cells (DC) immigrate into the CNS and function as antigen presenting cells (APCs), while the activated microglia emigrate from the brain to the periphery, transporting inflammation (Sfera et al, 2014 ; Sfera and Osorio, 2015 ). These findings provide an explanation for the previously observed impairment in peripheral immunity following CNS pathology such as strokes, neurosurgical interventions, Alzheimer's disease (AD) and schizophrenia (Hochmeister et al, 2008 ; D'Agostino et al, 2012 ).…”

“…For example, reactive astrocytes undergo hypertrophy (edema) probably in an attempt to erect an additional physical barrier and restrict the spread of infection (Majewska and Szczepanik, 2006 ). Astrocytic swelling due to aquaporin-4 (AQP-4) up-regulation was documented in SID and may explain why most known delirium biomarkers are released by astrocytes (Papadopoulos and Verkman, 2013 ; Sfera et al, 2014 ; Thrane et al, 2014 ).…”

“…This miR seems to block the transcription of CHRNA 7 gene which codes for alpha 7 nicotinic cholinergic receptors, while at the same time augments the expression of RNF-128, the Gene Related to Anergia in Lymphocytes (GRAIL), a gene involved in sepsis associated immune suppression (SAIS). Since SAIS represents a major cause of death in sepsis patients, miR-6775 may be a sepsis-stage marker in addition to a being a SID vulnerability screening tool (Sfera et al, 2014 ). We have hypothesized that delirium predisposing factors including low grade inflammation and the paucity of alpha 7 nicotinic acetylcholine receptors (nAChRs) may be the result of dysfunctional miR-6775 which silences the gene coding for these receptors.…”