Neurotransmitters as Immunomodulators

When you think of neurotransmitters, you probably thing of chemical messengers moving around the nervous system where they’re responsible for how you think, move, and feel. Most of us would be conformable in the knowledge that neurotransmitters drive the communication between neurons or between neurons and tissues and not much else. But that isn’t the whole story. A slew of discoveries over the past decade or so have been adding more and more to the role we thought neurotransmitters played, radically expanded our understanding and revealing their significant roles as modulators of the immune system.

Neurotransmitter Receptors, Meet Immune Cells

Historically, neurotransmitters were almost exclusively considered as messengers within the nervous system. We learned in school that neurotransmitters like acetylcholine (ACh) that activates muscle fibers, and serotonin (5-HT) that affects mood, rely on specific receptors on neurons or muscle cells, which make sure communication is accurate and precise. 

But after more detailed probing, not only have we learned that neurotransmitters do a lot more within the nervous system, but that immune cells also express corresponding receptors. Suddenly the narrowly defined remit of neurotransmitters became significantly broader. 

From earlier studies demonstrating expression of 5-HT receptors on immune cells (1) – the research began to gather momentum. For example, teams of scientists soon discovered that ACh can actually be synthesized in T cells (2), that CD4⁺ cells contain more ACh than either CD8⁺ or B cells, and that ACh synthesis and release from lymphocytes could be increased by mitogens (3). 

These and similar findings opened up a new level of understanding, and moved neurotransmitters from the realm of synaptic communication into a whole new arena where they’re also proving to be integral to immune cell behavior. 

Leukocytes: Neurotransmitter Releasers and Responders

One of the most significant developments in this field has been the recognition that leukocytes aren’t just passive recipients of neurotransmitter signals. We now know that immune cells like T cells and dendritic cells can synthesize and/or release ACh, dopamine, 5HT, and glutamate (4). This capability allows immune cells to engage in autocrine and paracrine signaling to modulate their own functions as well as those of nearby cells.

Dendritic cells, for example, don’t synthesize 5-HT themselves, but do express the 5-HT transporter, which allows them to take up 5-HT from their environment and release it to affect T cell activation during immune responses​ (5). Glutamate, the primary excitatory neurotransmitter, has also been demonstrated to be released by dendritic cells. Similar to 5-HT, glutamate release by dendritic cells modulates T cell activation, and occurs through a non-vesicular mechanism (6). 

Synapses formed between antigen presenting immunocytes and lymphocytes seem to concentrate neurotransmitter signals and stabilize subsequent interactions to support paracrine communication (7). And let’s not forget how neurotransmitters from sympathetic or parasympathetic nerves can alter the physiology of leukocytes in lymphoid tissues, adding another layer to this sophisticated network (4). These findings extend to other immune cell types and shine a light on a complex web of neurotransmitter signals we continue to untangle.

Modulating Macrophages

If we take a closer look at macrophages, we can start to really see neurotransmitters at work in the immune system. A group of researchers from Germany recently set out to see how the 5-HT7 receptor (5-HT7R) influences macrophage behavior. In this study they differentiated THP-1 cells into different macrophage subtypes to see what effect activating 5-HT7R with the agonist LP-211 had on these cells. 

They set the scene with western blotting and immunocytochemistry using our Anti-5HT7 Receptor/HTR7 (extracellular)-FITC Antibody (#ASR-037-F) and found 5-HT7R expression across all macrophage subtypes on both the cell surface and within intracellularly (Figure 1) (1). 

Figure 1. Representative images visualizing 5-HT7R localization using Anti-5HT7 Receptor/HTR7 (extracellular)-FITC Antibody (#ASR-037-F). Antibody specificity was confirmed using the 5HT7 Receptor/HTR7 (extracellular) Blocking Peptide (#BLP-SR037) (right panel; scale bars 20 μm).

From a more functional perspective, pharmacological activation of 5-HT7R led to significant changes in cell morphology and cytokine and chemokine secretion, along with reduced phagocytic activity and impaired migration – particularly in the M1-like macrophages. 

A series of other studies revealed how ACh influences the immune system through activation of nicotinic acetylcholine receptor on macrophage cells, where it induces anti-inflammatory effects (8, 9, 10).

Neurotransmitters in the Tumor Microenvironment

The tumor microenvironment (TME) is another interesting area where neurotransmitters modulate immune responses. In the TME, neurotransmitters interact with immune cells to influence tumor growth, progression, and metastasis (11). 

Catecholamine neurotransmitters, like norepinephrine and epinephrine, are well known for their role in the sympathetic nervous system’s fight-or-flight response. Yet in tumors they can promote an immunosuppressive environment by activating β-adrenergic receptors on immune cells. This action suppresses cytotoxic T cell and natural killer (NK) cell activity, which are important for anti-tumor immunity​ (12). 

Dopamine, known as a dominant neurotransmitter in the brain, has a more complex role in cancer where it modulate immune homeostasis to affect tumor growth and progression (11). Dopamine stimulates immune cells like macrophages, NK cells, and T cells to perform anti-tumor functions but has varying effects on T cells depending on the receptors involved. Dopamine activates resting T cells but inhibits activated ones, showing how these receptors have dynamic roles (13).

Applications in Research and Therapeutics

The more we understand the role of neurotransmitters in immune modulation, the more avenues of research and therapeutic interventions we open up. Antibodies that reliably target neurotransmitter receptors on immune cell surface will be lab workhorses when it comes to deciphering their role. 

At Alomone Labs we’ve developed range of antibodies against the extracellular domains of neurotransmitter receptors, including the 5-HT7 receptor, the β2-adrenergic receptor, the nicotinic ACh Receptor α7, and more. These antibodies, especially those conjugated directly to fluorophores, enable easy multiplexing and are ideal for live cell immunoassay techniques like flow cytometry and immunocytochemistry. Below, you can see a multicolor flow cytometry panel we created for these extracellular domain antibodies.

Figure 2. Multicolor flow cytometry in mouse J774 macrophages, using Anti-5HT7 Receptor/HTR7 (extracellular)-FITC Antibody (#ASR-037-F), Anti-β2-Adrenergic Receptor (extracellular)-PE Antibody (#AAR-016-PE), and Anti-Nicotinic Acetylcholine Receptor α7 (CHRNA7) (extracellular)-ATTO Fluor-633 Antibody (#ANC-007-FR). 

New Ideas and New Frontiers

As neurotransmitters firmly shift from working exclusively as neuronal messengers to being key players in the already-complex world of immunomodulation, we are given a host of new frontiers to explore. Whether you’re trying to understand the mechanisms and pathways at the core of immune responses or even looking at novel therapeutic targets, we all have more hypotheses than ever to start testing. It’s now up to you to unravel the interplay between the nervous and immune systems, and with help from robust and reliable reagents, we’re here to support you.

Alomone Labs products mentioned in this blog:

References

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