How Our Brain Can Fight Infection

Connecting the brain to the immune system

The brain has been proposed to act as the master regulator and modulator of the body, including our organ function and metabolism. This appreciation for the brain's ability to stimulate the immune system was realized by a pioneering study by Tracey and colleagues at the turn of the century when they showcased the vagus nerve's ability to attenuate inflammation to endotoxin, a key inflammatory molecule released by gram-positive bacteria during infection.¹

In their hallmark study, the team showcased that the electric stimulation of the peripheral vagus nerve in vivo during lethal endotoxemia in rats could prevent the development of shock by attenuating tumor necrosis factor (TNF) synthesis in the liver and subsequent levels within sera. This study opened the door to question how the nervous system, especially the vagus nerve, can modulate the immune system.

Since then, this neuroimmune crosstalk by which the neuronal and immune systems exhibit bidirectional interactions has been researched. More recently, it has been hypothesized that peripheral neurons and immune cells are colocalized and can affect each other within the tissue through mediators such as cytokines, neuropeptides, neurotransmitters and inflammatory mediators.

The brain regulates immunity

Recently, a study by Jin and colleagues published in Nature demonstrated that inflammatory responses to infection are regulated by a body-brain circuit orchestrated by the vagus nerve.² The authors show that a peripheral immune insult activates a brain-body axis that tightly regulates the inflammatory response through a specific neuronal subpopulation of the vagus nerve and brainstem. Cytokines play an important role between two subsets of vagal neuronal populations, creating either a proinflammatory or anti-inflammatory response. Neuronal subpopulations then check this response in the caudal nucleus of the solitary tracts (cNST) within the brainstem.

Two distinct vagal neuronal subsets were identified: TRA1-expressing neurons responding to anti-inflammatory cytokines and CALCA-expressing neurons responding to proinflammatory cytokines. These two neuronal subsets relay periphery information to the cNST in the brainstem to fine-tune the immune response by regulating dopamine β-hydroxylase (Dbh) expression. They further showcased the protective capabilities by activating TRA1⁺ vagal and Dbh-expressing cNST neurons in mice when challenged with sepsis or ulcerative colitis, which significantly improved survival.

Exploiting the brain-body axis

This new mechanistic insight may open new avenues for therapeutic intervention. The first question would be to understand how the peripheral immune system senses inflammation by the vagus nerve, which is integrated into the brainstem, and subsequent signals are transmitted back to the periphery to modulate the immune system and close the loop.

The next question is to understand which cytokines the vagus nerve is selecting to prompt this response. This also brings into question what other neuronal populations are interacting with the immune system as well, as these will need to be identified.

An understanding of these mechanisms would help build an understanding of how the nervous system plays a role in regulating both an over-reactive immune response, such as with autoimmune disease or cytokine storm, and under-reactive responses, such as immunodeficiencies and chronic infections. Pharmacologic targeting of this axis could help to alleviate these disorders by either upregulating or downregulating the immune response.

Peripheral neurons in neuroimmune crosstalk

Recent work in the field of neuroimmunology has identified that peripheral neurons (nociceptors) play a large role in the immune system by detecting harmful stimuli but also modulate the reaction to the immune system through the amplification or dampening of inflammation in a tissue- and context-dependent manner.³  

Nociceptors in the lung

Nociceptors in the gut

Neurons contribute to maintaining the intestinal barrier by stimulating mucus production from goblet cells through CGRP signaling, as well as playing a role in regulating the gut microbiome and protecting against inflammatory bowel diseases (IBD).

Nociceptors in wound healing

Nociceptor-derived signals help orchestrate the activities of neutrophils and macrophages through neuropeptide release, which promotes tissue repair and regeneration.

Interestingly, however, nociceptor interactions are also contradictory, as in certain infectious diseases, nociceptor signaling downregulates neutrophil requirements and benefits the infectious pathogen. An example of this was described by Baral and colleagues in a paper published in Nature Medicine in 2018.⁴ The authors found that TRPV1⁺ lung-innervating nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia through suppressing neutrophil recruitment and activation. This further solidifies the claim that peripheral neuron responses may be tissue-specific and the mechanisms between neuronal and immune cells are complex.

To be able to move towards a therapeutic avenue, the focus needs to be placed on elucidating the tissue-specific mechanism between the peripheral nervous system and the immune system. A mechanistic understanding will allow for therapeutics against viral and bacterial infections to tweak inflammation and can also help alleviate chronic diseases such as asthma and inflammatory bowel disease.