Antimicrobial anxiety: the impact of stress on antimicrobial immunity

Abstract

Leukocytes and epithelial cells are fundamental to antimicrobial immunity. Their antimicrobial responses are an evolutionarily conserved component of the innate immune system and are influenced by the host's response to external stimuli. The efficacy of host defense via antimicrobial responses derives from the ability of AMPs to rapidly identify and eradicate foreign microbes and activate proinflammatory pathways, and from the capacity of later innate and adaptive immune responses to amplify protection through distinct biochemical mechanisms. Recent advances in neuroimmunology have identified a direct link between the neuroendocrine and immune systems, where environmental stimuli are generally believed to promote a transient effect on the immune system in response to environmental challenges and are presumably brought back to baseline levels via neuroendocrine pathways. Stress is an environmental stimulus that flares from a variety of circumstances and has become engrained in human society. Small bouts of stress are believed to enhance the host's immune response; however, prolonged periods of stress can be detrimental through excess production of neuroendocrine-derived mediators that dampen immune responses to invasive pathogens. Elucidation of the mechanisms behind stress-induced immune modulation of antimicrobial responses will ultimately lead to the development of more effective therapeutic interventions for pathologic conditions. It is the intent of this review to broaden the existing paradigm of how stress-related molecules dampen immune responses through suppression of antimicrobial mechanisms, and to emphasize that bacteria can use these factors to enhance microbial pathogenesis during stress.

Figure 1.

Activation of stress pathways. Stress signals the brain to activate the three major neuroendocrine pathways: the HPA and the adrenergic and cholinergic pathways. Activation of the HPA promotes the release of GCs, and the activation of the adrenergic and cholinergic pathways promotes the release of NE/E and Ach, respectively. These molecules then act on distinct receptors expressed by a variety of tissues and cells that ultimately results in immunosuppression if prolonged.

Figure 2.

Suppression of cutaneous antimicrobial activity following stress. Release of stress hormones and neurotransmitters, such as Ach, GCs, NE/E, and CRH, from nerves and epithelial cells results in suppression of AMP expression and impaired barrier function at the interface between the skin barrier and external environment. Activation of neuroendocrine receptors on mast cells (MC) promotes degranulation, consequently depleting AMP stores, while releasing proinflammatory molecules that are believed to contribute to stress-induced skin diseases. AMPs and other factors liberated from dermal cells exacerbate inflammation further through vasodilation and protein extravasation, as well as through the induction of detrimental proinflammatory mediators.

Figure 3.

Suppression of intestinal antimicrobial activity by modifying bacterial virulence and iron stores. (A) Normally high-affinity, iron-binding proteins, such as Tf, prevent free iron (Fe) being made available to microbes to limit their growth and dissemination into exogenous tissues. Concentrations of catecholamines (NE; E) increase in the intestinal lumen following traumatic stress. (B) The catechol moiety acts as a magnet to mediate sequestration of iron from Tf and shift the balance to an iron-rich environment. Quarum-sensing mechanisms signals the bacteria to increase the expression of bacterial virulence factors, siderophores, which facilitate the internalization of iron liberated from Tf by NE/E. Ultimately, iron use allows for greater microbial growth and an increased capacity of the bacteria to adhere and possibly disseminate to distal sites to cause infection.

Figure 4.

Impact of stress on antimicrobial activity in immune cells. Physiological or PS promotes the secretion and release of neuroendocrine mediators, such as GCs, Ach, and catecholamines (NE; E). These molecules act on their respective receptors expressed on immune cells to suppress or enhance antimicrobial function and/or inflammation depending on the type of stress. Dysregulation of the antimicrobial activity may lead to a greater incidence of infection or inflammatory diseases. (A) Macrophage bactericidal capacity is diminished in addition to suppression of cytokine production when Ach receptors are activated. However, septic shock enhances macrophage antimicrobial activity, leading to an overload of proinflammatory mediators. (B) Neutrophil chemotaxis and bactericidal activity are reduced during periods of prolonged stress, although neutrophil infiltration is enhanced. (C) Keratinocyte expression of cathelicidin and defensins is reduced during chronic stress, in addition to a suppression of innate antimicrobial activity and lipid secretion. (D) Mast cell hyperplasia and greater tissue infiltration are evident during chronic stress, which implicate mast cells as an important contributor to stress-induced inflammation. (E) Receptor antagonists may be a useful treatment strategy, particularly for skin diseases, in patients with pathologic disease or infection caused by defects in antimicrobial protein regulation.