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

Sfera A, Cummings M, Osorio C - Front Med (Lausanne) (2015)

Bottom Line: 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.This gene favors regulatory T cells (Tregs), promoters of immunologic tolerance, which may predispose to both cancer and sepsis-induced immunosuppression.

View Article: PubMed Central - PubMed

Affiliation: Psychiatry, Patton State Hospital , Patton, CA , USA.

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.

No MeSH data available.


Related in: MedlinePlus

Activation of alpha 7-cholinergic nicotinic receptors (nAChR) on peripheral macrophages decreases cytokine synthesis exerting an anti-inflammatory effect (5). A similar cholinergic pathway, regulating microglial activation is operational in the CNS (6, 7).
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Figure 1: Activation of alpha 7-cholinergic nicotinic receptors (nAChR) on peripheral macrophages decreases cytokine synthesis exerting an anti-inflammatory effect (5). A similar cholinergic pathway, regulating microglial activation is operational in the CNS (6, 7).

Mentions: Recent studies demonstrate that aging is associated with lowered transcription of nAChRs with subsequent low-grade inflammation, as failure to properly activate alpha 7 nAChRs results in release of pro-inflammatory cytokines (Figure 1). For example, postmortem studies of human brains with Alzheimer’s disease (AD) reported up to 70% decrease in nAChRs expression (2). In addition, it was demonstrated that beta-amyloid itself can decrease transcription of nAChRs. With the same token, in sepsis, low expression of alpha 7 nAChRs on peripheral blood mononuclear cells is associated with uncontrolled inflammation and poor prognosis, suggesting age-related predisposition for sepsis (4). Furthermore, recent studies show that nicotine protects against septic injury by activation of alpha 7 nAChRs, which probably inhibits tall-like receptors 4 (TLR4) (5).


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

Sfera A, Cummings M, Osorio C - Front Med (Lausanne) (2015)

Activation of alpha 7-cholinergic nicotinic receptors (nAChR) on peripheral macrophages decreases cytokine synthesis exerting an anti-inflammatory effect (5). A similar cholinergic pathway, regulating microglial activation is operational in the CNS (6, 7).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543923&req=5

Figure 1: Activation of alpha 7-cholinergic nicotinic receptors (nAChR) on peripheral macrophages decreases cytokine synthesis exerting an anti-inflammatory effect (5). A similar cholinergic pathway, regulating microglial activation is operational in the CNS (6, 7).
Mentions: Recent studies demonstrate that aging is associated with lowered transcription of nAChRs with subsequent low-grade inflammation, as failure to properly activate alpha 7 nAChRs results in release of pro-inflammatory cytokines (Figure 1). For example, postmortem studies of human brains with Alzheimer’s disease (AD) reported up to 70% decrease in nAChRs expression (2). In addition, it was demonstrated that beta-amyloid itself can decrease transcription of nAChRs. With the same token, in sepsis, low expression of alpha 7 nAChRs on peripheral blood mononuclear cells is associated with uncontrolled inflammation and poor prognosis, suggesting age-related predisposition for sepsis (4). Furthermore, recent studies show that nicotine protects against septic injury by activation of alpha 7 nAChRs, which probably inhibits tall-like receptors 4 (TLR4) (5).

Bottom Line: 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.This gene favors regulatory T cells (Tregs), promoters of immunologic tolerance, which may predispose to both cancer and sepsis-induced immunosuppression.

View Article: PubMed Central - PubMed

Affiliation: Psychiatry, Patton State Hospital , Patton, CA , USA.

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.

No MeSH data available.


Related in: MedlinePlus