Hypothalamic-pituitary-adrenal axis immunity

Imura, H and Fukata, J., Endocrine-paracrine interaction in communication between the immune and endocrine systems. Activation of the hypothalamic-pituitary-adrenal axis in inflammation. Eur. J. Endocrinol. 130,32-37 (1994). 

Karrow, N. A., Activation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system during inflammation and altered programming of the neuroendocrine-immune axis... 

Experimental evidence suggests that sigma receptors play an important role in regulating and integrating both immune and endocrine functions. In experimental studies, it has been shown that the selective sigma ligand N-allyl-normetazocine stimulates the hypothalamic-pituitary-adrenal axis... 

The brain and the immune system are accepted as the two major body s adaptive systems (Elenkov et al., 2000). The brain can modulate immune functions and the immune system also sends messages to the brain. The communication between these two systems is done mainly by the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS). The sympathetic nervous system (SNS), which is part of the ANS, innervates the lymphoid organs (Elenkov et al., 2000) (Flierl et al., 2007). Catecholamines, like dopamine, serotonin, epinephrine and norepinephrine, are the end products of the SNS. 

Chrousos GP (1995) The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Eng J Med 332 1351-1362. 

C. Role of Hypothalamic-Pituitary-Adrenal Axis in Regulating Immunity... 

This, in turn, has led to investigation of OP-mediated suppression of the hypothalamic-pituitary-adrenal axis (Pena-Philippides et al., 2007). However, anti-ChEs were also found to initiate acute immune responses. For example, the nerve agent soman induces an increase in the pro-inflammatory cytokine TNFa, IL-lp, and fL-6 in rats, including in the brain, where IL-lp is thought to contribute to irreversible brain damage (Banks and Lein, 2012). This bidirectional impairment of immune functions may reflect systemic responses that affect more than the cholinergic system alone. 

The sympathetic nervous system (SNS) and the hypothalamic-pituitary axis work together as important modulators of the immune system after exposure to stressors. Norepinephrine (NE) and epinephrine (EPI) (catecholamines from the SNS) and neuroendocrine hormones modulate a range of immune cell activities, including cell proliferation, cytokine and antibody production, lytic activity, and migration. This chapter will focus on these two major pathways of brain-immune signaling, briefly summarizing the evidence for SNS and hypothalamic-pituitary-adrenal (HPA) modulation of immune function, their influence on immune-mediated diseases, immune modulation in aging, and early life influences on these pathways. 

Psychological stress may influence the immune system by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary axis (SAM). The well-described innervation of primary and secondary lymphoid tissues by the autonomic nervous system also has been implicated in stress-related modulation of the immune response. These pathways operate by producing biological mediators that interact with and affect cellular components of the immune system.13... 

Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol. 2005 18 41-78. 

Figure 18.2. Endocrine-immune inter-relationship in normal subject. The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are corticotrophin releasing factor (CRF), arginine vasopressin (AVP) and adrenocorticotrophic hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (e.g. hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

Lilly MP, Gann DS. The hypothalamic-pituitary-adrenal-immune axis. A critical assessment Arch Surg (United States) 1992 127 1463-74. 

It is now generally accepted that emotional/psychological stress stimulates the sympathetic nervous system, which in turn can lead to abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis [7]. During normal or abnormal times the HPA axis serves as a communicator between nervous, immune and endocrine systems. Thus, during stressful conditions abnormal secretions occur that can produce a variety of adverse effects upon various health states [7,8]. 

FI) male mice and divided them into two groups. One group was injected i.p. with zymosan to induce peritoneal inflammation and the other simultaneously with antalarmin, a CRH-1 receptor antagonist, to block hypothalamic-pituitary-adrenal (HPA) axis function. After 24 h of injection the mice were killed by CO2 asphyxia, and the peritoneal leukocytes (PTLs) isolated and counted. Additionally, the levels of ROS and COX activity were detected in PTLs by fluorometric and colorimetric assays, respectively. The result was that TTO inhalation led to a strong anti-inflammatory effect on the immune system stimulated by zymosan injection, whereas PTL number, ROS level, and COX activity in mice without inflammation were not affected. The HPA axis was shown to play an important role in the anti-inflammatory effect of TTO and antalarmin was observed to abolish the influence of inhaled TTO on PTL number and their ROS expression in mice with experimental peritonitis. In mice without inflammation these parameters were not affected. 

---