Introduction
Immunological system activation, challenge resolution, and host defense against potentially harmful inflammatory processes contribute to maintaining homeostasis during the immune challenge. Numerous protein hormones known as "cytokines" are released when the immune system is stimulated. Tumor necrosis factor-alpha, IL-1 (Interleukin - 1), Interleukin-6, and type I interferons (IFN) are proinflammatory cytokines that are part of the functional group of cytokines that mediates the innate immune response. Several cell types generate these cytokines in the initial phases of an immune response, including activated immune cells like macrophages (and their CNS counterparts, microglia), vascular endothelial cells, fibroblasts, and neurons.
The hypothalamic-pituitary-adrenal axis and the immune system communicate in both directions (human brain).
By acting on all three levels of the hypothalamic-pituitary axis, the immune system increases the release of glucocorticoids through early innate proinflammatory cytokines (TNF, IL-1, and IL-6) and interferons, as well as late acquired T cell cytokines (IL-2 and INF-). Further production and release of proinflammatory cytokines are suppressed by Glucocorticoid negative feedback on the immune system. Additionally, glucocorticoids significantly impact the development of downstream immune responses by triggering a switch from cellular (Th1/inflammatory) to humoral (Th2/anti-inflammatory) type immune responses. Glucocorticoids achieve this by shielding an organism from the negative effects of an excessive inflammatory immune response.
Glucocorticoids also significantly impact immune system development by regulating immune cell trafficking to sites of inflammation and changing adaptive immune responses that occur later by switching from cellular (Th1/inflammatory) to humoral (Th2/anti-inflammatory) type responses. In light of this, it is more accurate to think of glucocorticoids as immunomodulatory hormones rather than the traditional concept of them as immunosuppressant hormones. Depending on the immune response, immune compartment, and cell type, they can stimulate and suppress immune function.
What Is the Adrenal Axis?
The relationship between the hypothalamus, pituitary gland, and adrenal glands is known as the hypothalamic-pituitary-adrenal axis or hypothalamic-pituitary-adrenal axis. It is crucial to the body's response to stress. Cortisol is produced as a result of the axis route.
How Does The Hypothalamic Pituitary Adrenal Axis (HPA) Affect the Immune System?
The hypothalamic-pituitary-adrenal axis facilitates the systemic release of glucocorticoids in response to physiological and psychological stimuli Glucocorticoids. The multiple metabolic, cardiovascular, cognitive, and immunologic functions of Glucocorticoids and their practically universal expression mean that this system is crucial for the body's reaction to stress and maintaining homeostasis. Glucocorticoids have long been known to exert significant immunosuppressive and anti-inflammatory effects on almost all immune cells through various genomic and non-genomic pathways.
Multiple afferent sympathetic, parasympathetic, and limbic circuits directly or indirectly innervate the hypothalamus's paraventricular nucleus (for example, amygdala, hippocampus, and medial prefrontal cortex) and control the activity of the hypothalamic-pituitary-adrenal axis. The paraventricular nucleus functions as a crucial mediator in the modulation of the hypothalamic-pituitary-adrenal axis because it combines convergent stimulatory (catecholaminergic, glutamatergic, and serotonergic) or inhibitory (GABA-ergic) inputs. When the medial parvocellular division of the paraventricular nucleus secretory neurons is excited, either directly or through releasing inhibitory inputs, the hypothalamic-pituitary-adrenal axis is triggered.
As a result, the anterior pituitary gland's portal circulation releases arginine vasopressin and corticotropin-releasing hormone. These neuropeptides then cause the pituitary corticotrophs to release an adrenocorticotropic hormone into the bloodstream. The zona fasciculata of the adrenal cells then triggers the synthesis and systemic release of Glucocorticoids.
How Is The Hypothalamic Pituitary Adrenal Axis (HPA) Immunomodulatory During Viral Infection?
During viral infection, the hypothalamic-pituitary-adrenal axis is crucial for immunomodulation. Elevated plasma levels of glucocorticoid hormones, which can mediate adaptive behavioral, metabolic, cardiovascular, and immune system responses, are eventually brought on by activation of the hypothalamic-pituitary-adrenal axis. This review emphasizes how the hypothalamic-pituitary-adrenal axis influences viral pathogenesis and antiviral immunity.
Researchers have used the Newcastle disease virus, which does not actively infect the host, and polyinosinic polycytidylic acid (poly I: C), a synthetic double-stranded RNA used to imitate viral exposure, to study the effects of viral infection on hypothalamic-pituitary-adrenal axis function. Like lipopolysaccharide, poly I: C and Newcastle Disease Virus cause a noticeable hypothalamic-pituitary-adrenal axis response about 1-2 hours after injection. In contrast to an acute challenge like lipopolysaccharide, poly I: C, or Newcastle Disease Virus, the delayed cytokine response typically induced by a replicating virus (days as opposed to hours) does not interact with the hypothalamic-pituitary-adrenal axis similarly.
1. Polyinosinic - Polycytidylic Acid
Poly I: C has been used to imitate viral infection, just as lipopolysaccharide has been used to model the cytokine cascade during bacterial infection. When given systemically to mice or rabbits, poly I: C causes the hypothalamic-pituitary-adrenal axis to activate quickly (within 1-2 hours). Interleukin-6 in mice and CRH in rabbits have been necessary for this induced glucocorticoid response. Since Interleukin-6 knockout mice treated with poly I: C (as well as murine cytomegalovirus) show profoundly reduced corticosterone responses, as opposed to modest (but significant) decreases in lipopolysaccharide-treated mice and no significant reductions in restraint-stressed mice, the requirement for Interleukin-6 for glucocorticoid release appears to be specific for virus-type stimuli.
2. Newcastle Disease Virus (NDV)
Although some studies show peak adrenocorticotropic hormone/corticosterone responses around 8 h post-infection, Newcastle Disease Virus is a non-replicating virus that, like lipopolysaccharide and poly I: C, causes substantial elevations in these hormones about 2 h after intraperitoneal injection in mice or rats. The norepinephrine catabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG; at 2 hours post-injury), tryptophan, and the serotonin catabolite 5-hydroxy indole acetic acid (5-HIAA) are all present in higher amounts in the brain simultaneously with these neuroendocrine alterations (at 8 h p.i.).
Animals injected with virus-free supernatants derived from co-cultures of mouse spleen cells or human peripheral blood leukocytes with Newcastle Disease Virus also exhibited the Newcastle Disease Virus-induced adrenocorticotropic hormone/corticosterone response, demonstrating that the hypothalamic-pituitary-adrenal axis stimulation was caused by a substance released from the Newcastle Disease Virus-stimulated leukocytes and not by Newcastle Disease Virus itself. It was shown that Interleukin-1 was the most likely mediator of the Newcastle Disease Virus-induced adrenocorticotropic hormone/corticosterone response since pretreating the supernatant with Interleukin-1-antisera prevented its stimulatory effect on the hypothalamic-pituitary-adrenal axis in the Newcastle Disease Virus-injected rats. Additionally, the neuroendocrine and neurochemical reactions to Newcastle Disease Virus were blocked when the Interleukin-1 receptor antagonist (Interleukin-1ra) was administered to mice infected with Newcastle Disease Virus. CRH-Ab treatment and hypophysectomized animals eliminate the Newcastle Disease Virus-induced corticosterone response, proving the need for a healthy pituitary and CRH.
3. Murine Cytomegalovirus (MCMV)
A natural killer cell-mediated, early antiviral defense is induced by the cytopathic murine cytomegalovirus. High concentrations of interferons- generated by natural killer cells and Interleukin-12, as well as liver inflammation caused by natural killer cells, are indicators of the antiviral immune response. The innate immune response to murine cytomegalovirus infection also induces the proinflammatory cytokines tumor necrosis factor, Interleukin-1, and Interleukin-6 in addition to the aforementioned cytokines. Peak neuroendocrine (adrenocorticotropic hormone and corticosterone) responses (which happen at 36 hours after murine cytomegalovirus infection) and serum cytokine levels peak between 36 and 44 hours after infection. According to research by Ruzek et al., Interleukin- 6 is necessary for the murine cytomegalovirus-induced corticosterone response, and Interleukin-1 plays a role in Interleukin-6 production.
Increased serum levels of liver enzymes and the development of hepatic necrotic foci, both indicators of liver pathology, depend on tumor necrosis factor. Suppose glucocorticoids are removed by adrenalectomy (ADX); proinflammatory cytokine production, negatively regulated by glucocorticoids during murine cytomegalovirus infection, increases, as does splenic mRNA for a wider range of cytokines, including Interleukin-1 and. As a result, the mice die from septic shock. To restore survival in adrenalectomy mice with murine cytomegalovirus infection, corticosterone replacement or tumor necrosis factor-antisera treatment is required. Therefore, defense against tumor necrosis factor-mediated mortality during murine cytomegalovirus infection depends on the glucocorticoid response.
Conclusion
The precise signaling between the neurological, endocrine, and immune systems that results in adequate feedback (timing, amplitude, length, sensitivity, etc.) by Glucocorticoids is essential to prevent major negative effects for the brain elements after an immunogenic exposure, according to a wealth of experimental and clinical data. The "yin and yang" effects of the innate immune response in the brain may be significantly influenced by the effects of Glucocorticoids on the brain, especially those linked to their priming and pro-inflammatory qualities. Future research will be crucial in understanding the genetic and non-genomic mechanisms underpinning the endogenous and artificial Glucocorticoids' contextual remodeling of the brain's innate immune system.
