The role of the immune system in posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) develops in a subset of individuals upon exposure to traumatic stress. In addition to well-defined psychological and behavioral symptoms, some individuals with PTSD also exhibit elevated concentrations of inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Moreover, PTSD is often co-morbid with immune-related conditions, such as cardiometabolic and autoimmune disorders. Numerous factors, including lifetime trauma burden, biological sex, genetic background, metabolic conditions, and gut microbiota, may contribute to inflammation in PTSD. Importantly, inflammation can influence neural circuits and neurotransmitter signaling in regions of the brain relevant to fear, anxiety, and emotion regulation. Given the link between PTSD and the immune system, current studies are underway to evaluate the efficacy of anti-inflammatory treatments in those with PTSD. Understanding the complex interactions between PTSD and the immune system is essential for future discovery of diagnostic and therapeutic tools.

Fig. 1. Immune cells and cytokines implicated in PTSD.

Long dashed lines represent differentiation. Short dashed lines represent trafficking into the brain. BBB blood–brain barrier, IL interleukin, Th T helper cell, Treg regulatory T cell.

Fig. 2. Relationship between the HPA axis, sympathetic nervous system, and inflammation in PTSD.

Stress exposure stimulates sympathetic nervous system (SNS). Norepinephrine release from activated SNS fibers stimulates proinflammatory cytokines production through the NF-kB, B-Raf, and p38 pathways. The HPA axis is also activated upon exposure to stress, stimulating inflammatory responses that limit HPA reactivity. The reduced ability of glucocorticoids to inhibit inflammatory processes contributes to the proinflammatory environment in PTSD. CRH corticotrophin-releasing hormone, ACTH adrenocorticotropic hormone, NF-κB nuclear factor-κB, IL-1 Interleukin-1, IL-6 Interleukin-6.

Fig. 3. Trafficking of peripheral inflammatory signals to brain.

(1) Active transport of peripheral cytokines. (2) Passage of peripheral cytokines through leaky regions of blood–brain barrier (BBB). (3) Transmission of peripheral cytokine signals to the brain by activated cytokine receptors on afferent nerve fibers. (4) Trafficking of peripheral cell types (e.g., monocytes, macrophages, and T cells) in response to monocyte chemoattractant protein (MCP-1) release by activated microglia.

Fig. 4. Pro-inflammatory cytokine-induced changes in neurotransmitter systems.

Mechanisms by which proinflammatory cytokines affect the synthesis of monoamine neurotransmitters (i.e., serotonin and dopamine) are illustrated. BH4 tetrahydrobiopterin, IDO indoleamine 2,3-dioxygenase, KA kynurenic acid, NMDA N-methyl-d-aspartate, NO nitric oxide, NOS nitric oxide synthases, QUIN quinolinic acid, ROS reactive oxygen species.