Targeting the "cytokine storm" for therapeutic benefit

Abstract

Inflammation is the body's first line of defense against infection or injury, responding to challenges by activating innate and adaptive responses. Microbes have evolved a diverse range of strategies to avoid triggering inflammatory responses. However, some pathogens, such as the influenza virus and the Gram-negative bacterium Francisella tularensis, do trigger life-threatening "cytokine storms" in the host which can result in significant pathology and ultimately death. For these diseases, it has been proposed that downregulating inflammatory immune responses may improve outcome. We review some of the current candidates for treatment of cytokine storms which may prove useful in the clinic in the future and compare them to more traditional therapeutic candidates that target the pathogen rather than the host response.

Fig 1

During infection, the host recognizes the pathogen, which leads to cellular recruitment and a proinflammatory cytokine response including IL-6 and TNF-α. This inflammatory response leads to pathogen clearance, thus allowing the return to immune homeostasis and host survival. In some infections, immune recognition is delayed and/or evaded, causing a delayed and/or inappropriate response. This can allow the pathogen to proliferate, triggering hypercytokinemia that leads to tissue damage and potentially death of the host.

Fig 2

When a cytokine storm has arisen, conventional therapeutics may not be sufficient. Strategies to combat this cytokine storm have included compounds that target fundamental immune pathways, such as the chemokine network and the cholinergic anti-inflammatory pathway, and more specific strategies have included the use of HMGB1 antibodies and COX-2 inhibitors. All these lead to a downregulation of the cytokine storm, reducing the risk of tissue damage and allowing time for conventional therapies to target the pathogen directly.