Asthma and posttraumatic stress disorder (PTSD): Emerging links, potential models and mechanisms

Abstract

Posttraumatic stress disorder (PTSD) is a highly prevalent, debilitating mental health condition. A better understanding of contributory neurobiological mechanisms will lead to effective treatments, improving quality of life for patients. Given that not all trauma-exposed individuals develop PTSD, identification of pre-trauma susceptibility factors that can modulate posttraumatic outcomes is important. Recent clinical evidence supports a strong link between inflammatory conditions and PTSD. A particularly strong association has been reported between asthma and PTSD prevalence and severity. Unlike many other PTSD-comorbid inflammatory conditions, asthma often develops in children, sensitizing them to subsequent posttraumatic pathology throughout their lifetime. Currently, there is a significant need to understand the neurobiology, shared mechanisms, and inflammatory mediators that may contribute to comorbid asthma and PTSD. Here, we provide a translational perspective of asthma and PTSD risk and comorbidity, focusing on clinical associations, relevant rodent paradigms and potential mechanisms that may translate asthma-associated inflammation to PTSD development.

Figure 1:. Immune mechanisms active during allergic asthma response.

(1) Pathogen Associated Molecular Patterns (PAMPs) on inhaled allergens are recognized by Pattern Recognition Receptors (PRRs) expressed by airway epithelial cells, which produce cytokines and chemokines upon activation. (2) Chemokines, such as CCL20, recruit lung Dendritic cells (DCs) to the epithelial cell barrier where they encounter allergen and become activated. (3) Activated DCs migrate to the draining lymph node (LN) where they present allergen in the context of Major Histocompatability Class II molecules (MHCII) to activate naïve CD4+ T cells and induce differentiation into cytokine-producing effector T helper 2 (Th2) cells. (4) These Th2 cells produce IL-4, which induces B cells to class switch to IgE. (5) IgE produced by B cells binds to Fc𝜀RI on the surface of lung-resident mast cells. Once mast cell-bound IgE is crosslinked by allergen, mast cells can degranulate to release mediators, such as histamine, that induce inflammation and contribute to many of the hallmark airway symptoms of allergic asthma. (6) Activated, allergen-specific Th2 cells also migrate from the lymph node to the lung where they proliferate and produce IL-13 that acts upon epithelial cells to induce goblet cell hyperplasia and mucus production, and smooth muscle cells (SMC) to induce proliferation and mediate airway hyperresponsiveness (AHR). Th2 cells also produce IL-5, which recruits and prolongs the survival of eosinophils. (7) In severe asthma, Th17 cells also differentiate in the LN and migrate to the airways where they produce IL-17A, which both enhance the effects of IL-13, and recruit polymorphonuclear (PMN) cells to the airways.

Figure 2.. llustration of potential routes by which asthma-associated airway inflammation may impact brain physiology and behavior

(A) Pulmonary vagal-brain stem pathway: Afferent nerve fibers from sensory ganglia innervate pulmonary neuroendocrine cells. Intratracheal allergens and related inflammatory signals can activate vagal nerve afferents innervating brainstem nuclei that project to forebrain areas regulating emotional behavior, neuroendocrine and autonomic responses. (B) Sensory circumventricular organs: Fenestrated, “leaky”, blood vessels and peri-ventricular location allow CVOs to sense blood and CSF milieu and permit diffusion of cytokines and T cell extravasation. Presence of neuronal cell bodies projecting to forebrain-hindbrain centers controlling cardiovascular, neurovascular and behavioral responses makes CVOs particularly attractive in body-to-brain signaling. (C) Choroid plexus-blood-cerebrospinal fluid interphase. Specialized monolayer of epithelial cells (EC) facilitates the entry of adaptive immune mediators, particularly T cells from blood into the CSF compartment and interstitial spaces thereby modulating brain homeostasis and function. (D) Meningeal lymphatic system: Meningeal interphase provides a site for T cell diapedesis, as well as, T cell drainage from the CSF into cervical lymph nodes, providing an opportunity for generation and trafficking of reactive T cells into the parenchyma for modulating brain physiology and behavior.(E) Blood-brain barrier interphase: A protective barrier under homeostatic conditions, BBB integrity can be compromised by chronic exposure to pollutants, nanoparticles and stress. Elevated cytokine levels can increase BBB permeability by modifying tight junction proteins and endothelial cells allowing extravasation of immune mediators into the brain.