The immunology of sickness metabolism

Abstract

Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.

Keywords: Immunometabolism; immune system; infection; inflammasome; metabolic disease.

Fig. 1

Impact of infection on nutrient homeostasis. Infection can impact the regulation of systemic homeostasis in several ways. A Values of various parameters in the blood are maintained between threshold values. If blood values are outside of this homeostatic bandwidth, corrective action is undertaken. One way by which the immune system can mediate sickness metabolism following infection is by altering these threshold values. B Blood parameter homeostasis is regulated through a dynamic balance between the influx and efflux of nutrients. In this figure, blood glucose is given as an example. Infection can alter this balance in several ways. If threshold values are not altered, changes in nutrient flux are possible only if they are compensated for by equal and opposite alterations in other organs involved in maintaining homeostasis. In this example, reduced glucose uptake by skeletal muscle is compensated for by an increased flux of glucose to the immune system. C Changes in homeostatic regulation negatively impact normal organ function and are therefore not without risk. Strategies with a greater impact, such as changes in threshold levels, are therefore justified only if the risk of serious damage by the pathogen is high. Threats of a lower danger level will therefore have less impact on homeostasis, for example, by altering nutrient flux toward a single organ. Made with biorender.com

Fig. 2

Neuromodulation by the immune system. Although the nervous system is immune-privileged, it is not devoid of immunological control. Cytokines impact the central control of metabolism via cellular intermediates. (Left) Peripheral neuromodulation is mediated by neurons of the N. vagus, which are under the direct influence of cytokines produced in the periphery. These signals are sent to the hypothalamus, resulting in central regulation of sickness metabolism. (right) Central neuromodulation occurs directly in the brain. Immunological mediators can cross the endothelial barrier in the hypothalamus and reach microglia. These cells produce cytokines locally, thus amplifying the signal toward neurons. Endothelial cells (ECs) in the hypothalamus also sense cytokines and, in response, produce molecules such as PGE2. This leukotriene is sensed by neurons and mediates metabolic changes such as alterations in body temperature. Made with biorender.com

Fig. 3

Parallels between sickness metabolism following infection and in the context of metabolic disease. Obesity has a broad, detrimental impact on systemic metabolism and greatly increases the risk of developing metabolic syndrome (MetS). The immune system plays a role in the pathophysiology of most organs affected by MetS. The immune-mediated changes observed in the metabolically stressed organs are similar to those of some of the alterations observed after infection. This finding supports the hypothesis that metabolic disease is partially caused by a derailed immunological response against tissues in which metabolic stress is perceived as an infection. This dysregulated immune response leads to chronic metabolic changes normally associated with sickness metabolism. Made with biorender.com