Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger

Abstract

A considerable number of studies demonstrate that acute and chronic stressors prime CNS innate immune responses to subsequent pro-inflammatory challenges and that glucocorticoids mediate, in part, stress-induced sensitization of pro-inflammatory immune responses. Here, we explore the notion that GCs produce a persisting sensitization of CNS innate immune effectors (e.g. microglia) so that they will generate a potentiated pro-inflammatory response after the GC rise has dissipated, thereby enhancing the sickness response to infection or injury and maximizing the animal's ability to neutralize danger. The stress-induced GC response is conceptualized here as an neuroendocrine warning signal or alarmin to the innate immune system, which prepares or sensitizes the innate immune response to potential danger. Thus, a new understanding of the stress response and its function (priming CNS innate immune responses to infection or injury during a fight/flight emergency) would be suggested.

Keywords: Alarmin; Danger; Glucocorticoid; Microglia; Priming; Pro-inflammatory; Stress.

Fig. 1

Glucocorticoids (GCs) as a neuroendocrine alarm signal of danger. This model of stress-induced GC action on CNS innate immunity proposes that during the initial phase of a fight/flight response, the GC rise both inhibits inflammation and initiates a process that sensitizes CNS pro-inflammatory processes. These apparently contradictory actions of GCs can be conceptualized as an opponent-process. During the initial phase of a fight/flight response, GCs induce 2 opposing processes: (1) an anti-inflammatory process that predominates while GCs are highly elevated and (2) a latent process of microglial sensitization. After GC levels decrease below a threshold and are no longer anti-inflammatory, microglia sensitization persists to prepare the organism for a subsequent immunologic threat or danger (recuperative phase). If the organism is exposed to immunologic danger, a heightened CNS innate immune response will ensue, thereby enhancing the sickness response and immunologic defense against pathogens or sterile injury.