Chemical Neuroimmunology: Health in a Nutshell Bidirectional Communication between Immune and Stress (Limbic‐Hypothalamic‐Pituitary‐Adrenal) Systems

Abstract

Stress is a ubiquitous and pervasive part of modern life that is frequently blamed for causing a plethora of diseases and other discomforting medical conditions. All higher organisms, including humans, experience stress in the form of a wide variety of stressors that range from environmental pollutants and drugs to traumatic events or self-induced trauma. Stressors registered by the central nervous system (CNS) generate physiological stress responses in the body (periphery) by means of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. This LHPA axis operates through the use of chemical messengers such as the stress hormones corticotropin-releasing hormone (CRH) and glucocorticoids (GCs). Under conditions of frequent exposure to acute stress and/or chronic, long-term exposure to stress, the LHPA axis becomes dysfunctional and in the process frequently overproduces both CRH and GCs, which results in many mild to severely toxic side effects. Bidirectional communication between the LHPA axis and immune/inflammatory systems can dramatically potentiate these side effects and create environments in the CNS and periphery ripe for the triggering and/or promotion of tissue degeneration and disease. This review aims to present as far as possible a molecular view of the processes involved so as to provide a bridge from the diffuse range of studies on molecular structure and receptor interactions to the burgeoning biological and medical literature that describes the empirical interplay between stress and disease. We hope that our review of this fast-growing field, which we christen chemical neuroimmunology, will give a clear indication of the striking range and depth of current molecular, cellular and medical evidence linking stress hormones to degeneration and disease. In so doing, we hope to provide encouragement for others to become interested in this critical and far-reaching field of research, which is very much at the heart of many important disease processes and very much a critical part of the crucial interface between chemistry and biology.

Chronic mild stress impairs cognition in mice: From brain homeostasis to behavior

“…Activation of corticotropin-releasing hormone neurons stimulating the HPA axis is an established feature of major depression (Nemeroff, 1996). Furthermore, since TNF-α and IL-1β stimulate corticotropin-releasing hormone production (Lozovaya and Miller, 2003;Felder et al, 2003), their higher concentration presented in CMS may imply an intense stimulation of the HPA axis. This interaction influences downstream functions such as the release of corticosterone, and further regulation of immune factors (Wichers and Maes, 2002;Francis et al, 2003) also leading to alteration in neurogenesis and the subsequent cognitive impairments.…”

A Pilot Study Evaluating Presurgery Neuroanatomical Biomarkers for Postoperative Cognitive Decline After Total Knee Arthroplasty in Older Adults

“…ERC volume predicts conversion to AD, with smaller volumes having greater conversion rates (10)(11)(12). Because of its involvement in the limbichypothalamic-pituitary-adrenal axis, the hippocampus is vulnerable to neuronal degeneration after severe biological/psychological stress (13,14). Post-traumatic stress disorder associates with reduced hippocampal volumes (15,16), and hippocampal degeneration also occurs in rats after anoxia and mild hypothermia (17).…”

Inflammation and neuropeptides: the connection in diabetic wound healing

“…Also, cytokines have shown to directly lead to HPA-axis dysfunction, suggesting a bidirectional communication between inflammatory mediators and the HPA-axis (163). Glucocorticoids (GCs) such as cortisol are known to suppress inflammatory pathways and are known immunosupressants (164, 165). GCs secreted in response to acute, sub-acute and chronic stress suppress CD8 + cellular immunological responses but enhance CD4 + humoral-antibody immune responses (166, 167).…”

“…Similar to SP and CGRP, CRF stimulates the activation and degranulation of mast cells via the CRFR1 leading to histamine release (174). GCs suppress the activity of activator protein 1 (AP-1) and the transcription factor NF-κB (164). GCs inhibit IL-1, IL-6 and TNF-α and upregulate IL-4 and IL-10 (164).…”

“…GCs suppress the activity of activator protein 1 (AP-1) and the transcription factor NF-κB (164). GCs inhibit IL-1, IL-6 and TNF-α and upregulate IL-4 and IL-10 (164). In the CNS, CRF is known to induce IL-1 and in peripheral tissues stimulates the proliferation of B and T lymphocytes, induces IL-2 receptor expression, and releases IL-1 and IL-2 from mononuclear cells (164).…”