Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions

Abstract

Hematopoietic stem cells (HSCs) differentiate and generate all blood cell lineages while maintaining self-renewal ability throughout life. Systemic responses to stressful insults, either psychological or physical exert both stimulating and down-regulating effects on these dynamic members of the immune system. Stress-facilitated division and re-oriented differentiation of progenitor cells modifies hematopoietic cell type composition, while enhancing cytokine production and promoting inflammation. Inversely, stress-induced increases in the neurotransmitter acetylcholine (ACh) act to mitigate inflammatory response and regain homeostasis. This signaling process is terminated when ACh is hydrolyzed by acetylcholinesterase (AChE). Alternative splicing, which is stress-modified, changes the composition of AChE variants, modifying their terminal sequences, susceptibility for microRNA suppression, and sub-cellular localizations. Intriguingly, the effects of stress and AChE variants on hematopoietic development and inflammation in health and disease are both subject to small molecule as well as oligonucleotide-mediated manipulations in vitro and in vivo. The therapeutic agents can thus be targeted to the enzyme protein, its encoding mRNA transcripts, or the regulator microRNA-132, opening new venues for therapeutic interference with multiple nervous and immune system diseases.

Acetylcholinesterases of blood-feeding flies and ticks

“…AChE is known to be secreted by other parasites [22,23], including the saliva of blood feeding insects [24,25]. AChE is known to be involved in vertebrate immune function [26,27], and secretion of AChE in tick saliva may be involved in promoting feeding by hydrolyzing platelet activating factor [24], or inhibiting infiltration of lymphocytes [28] and wound healing [29] by reducing local tissue concentration of acetylcholine. In addition, salivary AChE may provide modulation of the host immune response [30][31][32], or protection of the tick from effects of acetylcholine contained in the large volume of ingested blood from the host.…”

“…AChE is known to be involved in vertebrate immune function [26,27], and secretion of AChE in tick saliva may be involved in promoting feeding by hydrolyzing platelet activating factor [24], or inhibiting infiltration of lymphocytes [28] and wound healing [29] by reducing local tissue concentration of acetylcholine. In addition, salivary AChE may provide modulation of the host immune response [30][31][32], or protection of the tick from effects of acetylcholine contained in the large volume of ingested blood from the host. The phylogram depicting amino acid sequences purportedly encoded by AChE genes of I. scapularis and confirmed AChEs of R. microplus shown in Fig.…”

Identification of CD14 transcript in blood polymorphonuclear neutrophil leukocytes and functional variation in Holsteins

“…This can affect the function and intracellular distribution of proteins, which is important during cellular differentiation and development, for physiological functions, and in pathological states (Eizirik et al, 2012;Gilboa-Geffen et al, 2012). In previous studies we showed that immune-related genes play important roles in bovine mastitis via alternative splicing (Huang et al, 2011;Hou et al, 2012;Li et al, 2013;Wang et al, 2014;Zhang et al, 2015).…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…One possible mechanism involves the interaction of AChE-S with the anti-apoptotic C-terminal binding protein (CtBP), thus reducing T lymphopoiesis, in contrast to the effect of AChE-R, which upregulates haematopoiesis (Gilboa-Geffen et al, 2012).…”

“…These events result in over-production of AChE and replacement of the synaptic AChE (AChE-S, the major stable AChE splice variant) by the less stable read through (AChE-R) variant (Gilboa-Geffen et al, 2012), which displays morphogenic functions in multiple embryonic and tumour cells (Grisaru et al, 2006). Under stress responses, blood AChE-R undergoes C-terminal cleavage to release the C-…”