Neuro-Immune Interactions: Connecting the Nervous and Immune Systems
The complexity biology and signaling processes within the body have always amazed me. During grad school, one of my professors briefly mentioned a neuro-immuno loop, a connection between the immune system and the nervous system. I had previously thought of these two body systems as separate entities, each doing its own function. Being an immunology grad student, I hadn’t given much thought to the nervous system. But the idea that the two systems were connected was fascinating, especially since I had recently experienced stress-induced hives. While I was aware that stress had a neurological impact and hives were due to an immune response, I hadn’t fully put two and two together and wasn’t fully aware of the connection between the nervous system and the immune system.
Since my grad school experience, the body of research on this neuro-immune relationship has progressed, and the field has shown that the two systems play important roles in regulating each other. In many ways, the connection between the immune system and the nervous system makes sense, since both are responsible for sensing and reacting to environmental conditions or threats. While this is still a developing research area, I’ve highlighted below some of the findings on the connections between these two systems.
One major way that the nervous system impacts the immune system is through the placement of nerves in key immune organs. This innervation appears to help regulate a variety of facets of the immune system. For example, sympathetic nerves are present in the bone marrow, the gestation location of the hematopoietic stem cells (HSCs) that give rise to the body’s immune cell repertoire. In the bone marrow, these nerves regulate the release of the HSCs through a variety of mechanisms including by the production of certain compounds. These neuronally-derived compounds, including neuropeptide Y, substance P, and neurokinin A, can trigger the release of HSCs and trigger the production of cytokines involved in HSC development and differentiation.
Similarly, innervation in the secondary lymphoid organs, such as the spleen, allows for additional neuronal feedback to the immune system. In the spleen, the splenic nerve is responsible for a significant portion of these neuronal signals. Through a cycle of signaling involving norepinephrine and cholinergic signals, the splenic nerve can regulate the activation of resident macrophages, a key immune cell type. Additionally, neurons can produce compounds called neuropeptides that impact immune cell function in the spleen. Neuropeptide Y has been shown to control T and B cell expansion, as well as antibody production. Similarly, neuron-derived substance P can increase the expression of IL-2, IL-4, and IFN-gamma to induce immune cell proliferation. These and other neuropeptides also regulate inflammation, being pro-inflammatory and anti-inflammatory depending on the specific contexts. Neuronal compounds are also impactful in other secondary lymphoid organs, like the lymph nodes. Norepinephrine has been demonstrated to be important for proper antigen processing and T cell function.
The influences of the nervous system on the immune system are equally apparent in our organs that interact with the outside world: the intestines and the lungs.
The largest compartment of immune cells can be found in the intestine, which also has as many neurons as the spinal cord. Neuronal release of norepinephrine can activate cytokine production by T cells, induce B cell proliferation, and trigger antibody production. The enteric neurons can also regulate the innate immune system, including through neuropeptide production and nicotinic acetylcholine receptor signaling. Similarly, the lung possesses an extensive network of nerve fibers throughout the respiratory tissue. The nervous system cells in and around the lungs can release acetylcholine, which binds to receptors called muscarinic receptors on immune cells to promote inflammation.
Importantly, the interaction between our immune and nervous systems is a two-way street, and the immune system is able to influence our neurons. Immune cells can secrete chemical signals, including neurotransmitters, that can induce specific reactions from neurons. T cells, for example, can produce cytokines that can activate sensory neurons in the skin, producing an itch. In the lung, as another example, activation of sensory neurons by immune cell-derived cytokines can result in a cough during lung infections.
Researchers have also worked to identify and characterize the specific cell-cell interactions that occur during the crosstalk between these two bodily systems. Neurons, it turns out, can communicate with a variety of immune cells, impacting their function in specific ways. In certain situations, neurons can release noradrenaline which prevents the recruitment, activation, and function of neutrophils, the body’s rapid response immune cells to sites of infection. Neurons can also release a protein called CGRP, which can prevent neutrophil recruitment and activation to tamp down the immune response to certain bacteria. While it may appear counterintuitive that they body is hindering its ability to fight infection, it may be a way for the body to calibrate the immune response to prevent excessive inflammatory damage. Interestingly, neurons can also promote inflammation, such as in the case of certain skin infections. However, the full understanding of the contextual cues that mediate these differences has yet to be determined.
As mentioned above, neurons can communicate with a variety of immune cells, including T cells, B cells, macrophages, and neutrophils. Neurons can also influence mast cells, the immune cells involved in allergic reactions. Neurons can release a host of neuropeptides that bind to mast cells and trigger their activation and subsequent degranulation, which is when the mast cell releases a host of proteins into its surroundings. These factors include histamine and are responsible for a lot of the symptoms we associate with allergies. Additionally, stress, it turns out, can trigger the release of these neuropeptides from neurons, activating the mast cells and producing allergy symptoms, likely explaining the event that led to my initial interest in these pathways mentioned in the opening paragraph.
As you can see, the communication between the nervous and immune systems can be complex, and sometimes in complexity, things break down. Dysfunction in the neuro-immune crosstalk has been associated with a variety of diseases. Patients with Crohn’s disease, for example, exhibit altered innervation of the intestine. This is thought to interrupt the normal communication between the nervous system and the immune system, potentially contributing to the inflammation seen in the disease. Immune factors, like cytokines, can also influence the nervous system during disease states. Proinflammatory cytokines, when released during infection, can result in behavioral changes, such as fever and lethargy. In the brain, IFN-gamma can impact the signaling between prefrontal cortex neurons, contributing to behavioral changes. Another inflammatory cytokine, IL-17, has been shown to play a role in autism spectrum disorders, schizophrenia, and multiple sclerosis. Understanding how immune factors influence neurons and vice versa could provide important clues for developing novel therapeutic strategies for treating diseases.
As is always the case, as this field continues to grow, more questions arise as researchers work to unravel the complexities of these systems. By better understanding the key pathways and interactions between immune cells and neurons, we may be able to better understand how the body fights diseases and interacts with its environment. It’s always fun to learn more about how our bodies work.
This post was inspired and informed by: Godinho-Silva, C; Cardoso, F; and Veiga-Fernandes, H. Neuro-Immune Cell Units: A New Paradigm in Physiology. Annu. Rev. Immunol. 2019. 37:19-46.
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