Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

Abstract

In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including α7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M(1)/M(5) mAChR signaling up-regulates IgG(1) and pro-inflammatory cytokine production, while α7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric α7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating α7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation.

Molecular and Functional Neuroscience in Immunity

“…The availability of molecular sensors for detecting pathogen fragments and inflammatory molecules on both neurons and immune cells allows their simultaneous involvement in inflammatory responses (42). Immune cells utilize their additional neuron-like “equipment” in close-range paracrine inflammatory regulation and in relay mechanisms in neuroimmunomodulatory circuits (39, 40). Thus, the nervous system and the immune system that evolved seemingly different regulatory mechanisms can join forces in defense against dangers of life-threatening proportions.…”

Cholinergic modulation of the immune system presents new approaches for treating inflammation

“…An explanation for this discrepancy has been provided by recent evidence that many immune cells, particularly T and B cells can exhibit a cholinergic phenotype (Kawashima et al, 2012; Kawashima et al, 2015; Reardon et al, 2013; Rosas-Ballina et al, 2011). Identification of these cells in situ had been difficult since most available antibodies have a low efficacy for labeling ChAT in the periphery.…”

Inhibition of 2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice

“…These changes occur at both inflamed and noninflamed sites of the gut and result in secretion and motor abnormalities, which contribute to the wide-ranging clinical symptoms such as abdominal discomfort, bloating, and diarrhea (Blandizzi et al, 2003;Hons et al, 2009). However, the communication between the autonomic nervous system and immune system is bidirectional, and not only inflammatory mediators induce neuronal responses, but also acetylcholine (ACh) and catecholamines modulate directly the functions of macrophages, neutrophils, and lymphocytes (recently reviewed by Di Giovangiulio et al, 2015;Kawashima et al, 2015;Pavlov and Tracey, 2015). Hence, pharmacological targeting of these neuro-immune cell interactions provides a novel approach to suppress intestinal inflammation.…”