Experimental Human Endotoxemia, Sickness Behavior, and Neuropsychiatric Diseases

Abstract

Systemic inflammation is among the most prominent and most frequently observed responses of the immune system. From everyday challenges like mild infections to severe forms such as chronic inflammatory diseases or sepsis, inflammatory states can develop in many ways over the lifespan. Over the past few decades, it has become clear that inflammatory events can have a strong impact on brain functions. Inflammatory mediators released by activated immune cells induce not only adaptive behavioral responses such as sickness behavior but also can lead to cognitive impairment and may even promote the development of mood disorders. Since most of these aspects cannot be sufficiently modeled in laboratory animals, there is a need for experimental inflammatory models in humans. Intravenous or intramuscular injection of bacterial lipopolysaccharide (LPS, endotoxin) represents a model to induce transient systemic low-grade inflammation in healthy human subjects. During the past two decades, this model has been increasingly used for psychoneuroimmunology (PNI) research. After a brief introduction into sickness behavior and the history of immune-to-brain research, we will summarize work employing this promising model beginning with the first studies on sleep alterations and ending with studies on social behavior using cutting-edge neuroimaging techniques like functional magnetic resonance imaging (fMRI) or positron emission tomography (PET). We will discuss potential difficulties and limitations of the model and provide implications for future studies. In addition we give a short exposition on the immunologic properties of LPS, information pathways from the immune system to the brain, and on the cytokine hypothesis of depression. Systemic inflammation is among the most prominent and most frequently observed responses of the immune system. From everyday challenges like mild infections to severe forms such as chronic inflammatory diseases or sepsis, inflammatory states can develop in many ways over the lifespan. Over the past few decades, it has become clear that inflammatory events can have a strong impact on brain functions. Inflammatory mediators released by activated immune cells induce not only adaptive behavioral responses such as sickness behavior but also can lead to cognitive impairment and may even promote the development of mood disorders. Since most of these aspects cannot be sufficiently modeled in laboratory animals, there is a need for experimental inflammatory models in humans. Intravenous or intramuscular injection of bacterial lipopolysaccharide (LPS, endotoxin) represents a model to induce transient systemic low-grade inflammation in healthy human subjects. During the past two decades, this model has been increasingly used for psychoneuroimmunology (PNI) research. After a brief introduction into sickness behavior and the history of immune-to-brain research, we will summarize work employing this promising model beginning with the first studies on sleep alterations and ending with studies on social behavior using cutting-edge neuroimaging techniques like functional magnetic resonance imaging (fMRI) or positron emission tomography (PET). We will discuss potential difficulties and limitations of the model and provide implications for future studies. In addition we give a short exposition on the immunologic properties of LPS, information pathways from the immune system to the brain, and on the cytokine hypothesis of depression.