Trends in Immunology
Feature ReviewThe ‘cytokine storm’: molecular mechanisms and therapeutic prospects
Section snippets
The cytokine storm and cell death
The term ‘cytokine storm’ (CS) has been increasingly used in both the scientific literature and public media to denote an out-of-control inflammatory response, although a specific molecular definition to delineate CS from normal inflammation and to describe the amounts and types of cytokines involved has remained elusive. The term CS was first used during the early 1990s to describe the effects of graft-versus-host disease (GvHD) [1,2] and later, in the infectious disease setting, during the
Stimuli that trigger the CS
Multiple stimuli can result in CSS with largely similar clinical manifestations (Table 2). Based on the source of the stimulus, a CS can be broadly classified into pathogen-induced CS (sepsis), autoinflammatory or monogenic CS, or therapeutic intervention-induced CS. Understanding the underlying mechanisms linking these stimuli to the CS is important to identify the molecular pathways involved.
Molecular mechanisms of a CS
CSS can be induced by diverse stimuli through shared signaling pathways; innate immune PRR sensing of PAMPs or DAMPs activates downstream molecular pathways that are conserved across stimuli and mammalian species [43]. The host innate immune response to infection or sterile insults provides the first line of defense against damage and activates major signaling pathways for the production of inflammatory cytokines and chemokines (Figure 1). These cytokines are crucial for clearing infections and
Therapeutics to treat a CS
Thus far, treatment of a CS has been largely aimed at maintaining critical organ function by limiting the collateral damage caused by an activated immune system. Although general immunosuppression was initially considered as a potential strategy in CSS, a deeper mechanistic understanding of the pathways involved has highlighted the failures of general immunosuppression and suggested more-targeted therapies as a superior approach. Corticosteroids, such as glucocorticoids and dexamethasone, act
Concluding remarks
Innate immune cells, such as macrophages, dendritic cells, and NK cells, release proinflammatory cytokines in response to infectious and sterile insults. The initial inflammatory response is crucial to clear the infection; however, a dysregulated inflammatory response can cause a CS, potentially leading to tissue and organ damage, and mortality. CS can also occur in response to some therapeutic interventions and underlying conditions during cancer and autoinflammation. Here, we have reviewed
Acknowledgments
We appreciate all those who have contributed substantially to the study of cytokine biology to build the foundation that has enabled us to demonstrate and define a CS. We apologize to our colleagues in the field whose work could not be cited due to space limitations. We thank K. Nichols for her insightful comments and feedback, all members of the Kanneganti laboratory for their comments and suggestions, and R. Tweedell for scientific editing and writing support. Work from our laboratory is
Declaration of interests
St. Jude Children’s Research hospital filed a provisional patent application on TNF-α and IFN-γ signaling, listing R.K. and T.-D.K. as inventors (serial no. 63/106,012).
Glossary
- Acute respiratory distress syndrome (ARDS)
- life-threatening lung injury caused by low oxygen concentrations in the blood as a result of fluid build-up in alveoli.
- Alarmins
- DAMPs, such as HMGB1 or IL-1α; released by damaged or necrotic cells.
- Autoinflammation
- caused by overactivation of the innate immune system with little or no evidence of a specific adaptive immunity, such as autoreactive T cells or autoantibodies.
- Chimeric antigen receptor (CAR) T cells
- T cells that have been engineered with a
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