A Healthy Inflammatory Response Depends on Neuroendocrine Balance

The immune system protects the body, providing defense against foreign invaders and other immune challenges. One of the immune system’s main weapons is the inflammatory response.¹ This involves inflammatory mediators such as the cytokines, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). These substances interact with neurotransmitters and the nervous system to impact neuro-immune activity.² For example, inflammation can decrease the firing rate of neurons in the frontal lobe, preventing communication between the brain and the enteric nervous system.^3,4 Inflammation can impact everything from mood to respiratory and cardiovascular health to blood sugar balance.⁵

This blog summarizes some of the interactions between neurotransmitters, adrenal hormones and inflammation.^6,7

Neurotransmitters and the Inflammatory Response

Serotonin

Inflammation is often associated with changes in mood.⁸ Serotonin is also associated with mood as well as sleep. The interactions between serotonin and inflammation are reciprocal, with each impacting the other in a continuous feedback loop.

Inflammation can impact serotonin levels and receptors. Tryptophan is the amino acid precursor to serotonin. Proinflammatory cytokines such as interleukin-6 (IL-6), IFN-γ, and TNF-α cause tryptophan depletion via activation of the kynurenine and quinolinic acid pathways⁹ thus making less tryptophan available for serotonin synthesis. Tryptophan depletion can lead to a reduction in serotonin.¹⁰ On the other hand, serotonin can influence immune activity. For example, a 2008 study points out that agonists for serotonin receptor subtype 2A (5-HT2A) can block the pro-inflammatory effects of TNF.¹¹

Glutamate

Glutamate is the brain’s main excitatory neurotransmitter, maintaining the alert and awake state. It is also involved in learning and memory. Excess levels can be excitotoxic. That is, too much glutamate can contribute to neuronal death.

Glutamate acts as an agonist on metabotropic glutamate receptors (mGluR). These receptors are found on T cells, major players in the adaptive immunity branch of the immune system. Researchers suggest that the presence of mGluR on T cells may allow glutamate to modulate T cell-mediated immune responses.¹²

Dopamine

Dopamine is the key neurotransmitter in the pleasure-reward pathway. Associated with feelings of joy, dopamine plays a large role in cravings, libido, and salience.

The presence of dopamine can decrease the inflammatory response. Dopamine inhibits inflammasomes, key signaling molecules that detect pathogenic microorganisms and activate highly pro-inflammatory cytokines such as IL-1β and IL-18. In one study, researchers suggest dopamine and activation of the dopamine receptor, DRD1, can inhibit the inflammasome NLRP3 necessary for an inflammatory response.¹³

Norepinephrine

In the brain, norepinephrine is important for focus, concentration, motivation and drive.

Norepinephrine also plays an anti-inflammatory role.¹⁴ For example, when norepinephrine binds to β-adrenergic receptors on intestinal lymphocytes, it causes suppression of cytokines: TNF-α, interleukin-1 beta (IL-1β), and IFN-γ.^15,16 Norepinephrine also works with acetylcholine to reduce generalized inflammation.¹⁷

Epinephrine

Epinephrine is the last catecholamine produced in the catecholamine pathway, which includes dopamine and norepinephrine. Also known as adrenaline, epinephrine is the major fight-or-flight neurohormone, helping the body prepare for stressful situations.

Epinephrine has been shown to have anti-inflammatory activity. For example, Ağaç, et al, suggest that controlling immune function via epinephrine signaling can downregulate inflammatory cells that secrete IFN-γ and TNF-α and induce type I IFN within air pathways.¹⁸

We can conclude from our review that proper catecholamine balance aids in the prevention of inflammation.

GABA

GABA is the primary inhibitory neurotransmitter. GABA is important for promoting calm and relaxation.

The GABA-A receptor expressed on T-cells, has immunoinhibitory effects. For example, GABA has been shown to have inhibitory effects on myelin proteins in models of autoimmune MS.¹⁹

Adrenal Hormones and the Inflammatory Response

DHEA/DHEA-S

DHEA-S also plays an important inhibitory role in inflammation.²⁰ DHEA has been shown to reduce microglia-induced inflammation both in vitro and in vivo.²¹ Rodent studies show supplementation with DHEA reduces TNFα, IL-6 and NFκ-B.^22-24

Cortisol

Cortisol is the body’s main stress hormone, which rises in response to stress. Cortisol is also one of the body’s primary anti-inflammatory hormones.²⁵ Stressors, including inflammation in some cases, upregulate the HPA axis, increasing cortisol levels.

Cortisol binds to glucocorticoid receptors on immune cells, suppresses cytokine production and neutrophil and macrophage trafficking, and inhibits natural killer cells as well as B and T cells. However, sustained elevated levels of cortisol or an elevated cortisol:DHEA ratio can result in unwanted immunosuppression and create a domino effect throughout the Neuroendocrine System that can have negative ramifications.^26,27

Neuroendocrine Balance is Critical for a Healthy Inflammatory Response

Neuroendocrine balance is crucial due to the direct effects it has on the immune system. Understanding the interactions between the nervous, endocrine, and immune systems are key in optimizing immune system function and reducing inflammation.

If inflammation is present, it is valuable to assess neurotransmitter and adrenal hormone balance. The HPA and HPA-G Complete profiles assess neurotransmitters, adrenal hormones, and sex hormones which can be associated with inflammation.

If you are a patient interested in testing, find a provider near you. If you are a practitioner, set up an account or log in to order.

References

1. Hakansson A, Molin G. (2001). Gut Microbiota and Inflammation. Nutrients, 637-682.
2. Bush B. (2013, July 1). Neurotransmitters Immune Effects: a whole body approach. Retrieved from Naturopathic Doctor news and review: https://ndnr.com/pain-medicine/neurotransmitter-immune-effects/#
3. Sanesco Health . (2014). The Communication System. In S. International, Technical Guide (pp. 5-58). Asheville.
4. Pongratz G, Straub RH. (2014). The Sympathetic nervous response in inflammation. Arthritis research & therapy, 504.
5. Kornfeld RA. (2011, November 11). Huffpost. Retrieved from Five ways to reduce inflammation naturally: https://www.huffingtonpost.com/dr-robert-a-kornfeld/5-ways-to-reduce-inflamma_b_271640.html
6. Hansen F. (2018). Adrenal Fatigue and your Immune System. Retrieved from The Adrenal Fatigue Solution: https://adrenalfatiguesolution.com/immune-system/
7. Kipper-Galperin M, Galilly R, Danenberg HD, Brenner T. (1999). Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interlukin-6 in astrocytes. International journal of Developmental Neuroscience, 765-775.
8. Mangge H, Stelzer I, Reininghaus EZ, et al. Disturbed tryptophan metabolism in cardiovascular disease. Curr Med Chem. 2014 Jun;21(17):1931-7.
9.  Ibid.
10. Jenkins TA, Nguyen JC, Polglaze KE, et al. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016 Jan 20;8(1). pii: E56. doi: 10.3390/nu8010056.
11. Pelletier, M., & Siegel, R. M. (2009). Wishing Away Inflammation? New Links between Serotonin and TNF signaling. Molecular Interventions, 299-301.
12. Pacheco R, Ciruela F, Casadó V, et al. Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation. J Biol Chem. 2004 Aug 6;279(32):33352-8.
13. Yan Y, Jiang W, Liu L, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015 Jan 15;160(1-2):62-73. doi: 10.1016/j.cell.2014.11.047.
14. Ağaç D, Gill MA, Far J D (2018). Adremergic Signaling at the Interface of Allergic Asthma and Viral Infections. Frontiers in Immunology, 736.
15. Swanson MA, Lee WT, Sanders VM. IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol. 2001 Jan 1;166(1):232-40.
16. Padro CJ, Sanders VM. (2014). Neuroendocrine regulation of inflammation. Seminars in Immunology, 357-368.
17. Guyot M, Simon T, Panzolini C, et al. Apical splenic nerve electrical stimulation discloses an anti-inflammatory pathway relying on adrenergic and nicotinic receptors in myeloid cells. Brain Behav Immun. 2019 Aug;80:238-246. doi: 10.1016/j.bbi.2019.03.015.
18. Ağaç D, op. cit.
19. Bhat R, Axtell R, Mitra A, et al. Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2580-5. doi: 10.1073/pnas.0915139107.
20. Koziol-White CJ, Goncharova EA, Cao G, et al. DHEA-S inhibits human neutrophil and human airway smooth muscle migration. Biochim Biophys Acta. 2012 Oct;1822(10):1638-42. doi: 10.1016/j.bbadis.2012.06.012.
21. Alexaki VI, Fodelianaki G, Neuwirth A, et al. DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway. Mol Psychiatry. 2018 Jun;23(6):1410-1420. doi: 10.1038/mp.2017.167.
22. Komine S, Akiyama K, Warabi E, et al. Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis. Sci Rep. 2017 Sep 20;7(1):11977. doi: 10.1038/s41598-017-12358-8.
23. Danenberg HD, Alpert G, Lustig S, Ben-Nathan D. Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production. Antimicrob Agents Chemother. 1992;36:2275–2279. doi: 10.1128/AAC.36.10.2275.
24. Ben-Nathan D, Padgett D A, Loria RM. Androstenediol and dehydroepiandrosterone protect mice against lethal bacterial infections and lipopolysaccharide toxicity. J Med Microbiol 48. (1999):425–431.
25. Hannibal KE, Bishop MD. Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation. Phys Ther. 2014 Dec;94(12):1816-25. doi: 10.2522/ptj.20130597.
26. Butcher SK, Killampalli V, Lascelles D, et al. Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell. 2005 Dec;4(6):319-24.
27. Adam EK, Quinn ME, Tavernier R, et al. Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. Psychoneuroendocrinology. 2017 Sep;83:25-41. doi: 10.1016/j.psyneuen.2017.05.018. 24.