| Summary: | Inflammation, an essential cytokine-mediated process for generating a neutralising immune response against pathogens, is generally protective. However, aberrant or excessive production of proinflammatory cytokines is associated with uncontrolled local and systemic inflammation, resulting in cell death and often irreversible tissue damage. Uncontrolled inflammation can manifest over timescales spanning hours to years and is primarily dependent on the triggering event. Rapid and potentially lethal increases in cytokine production, or ‘cytokine storm’, develops in hours to days, and is associated with cancer cell-based immunotherapies, such as chimeric antigen receptor T-cell therapy. On the other hand, some bacterial and viral infections with high microbial replication or highly potent antigens elicit immune responses that result in supraphysiological systemic cytokine concentrations, which manifest over days to weeks. Immune dysregulation in autoimmune diseases can lead to chronic cytokine-mediated tissue damage spanning months to years, which often occurs episodically. Upregulation of IL-1, IL-6, IFN-γ, TNF, and granulocyte macrophage colony-stimulating factor frequently coincides with cytokine storm, sepsis, and autoimmune disease. Inhibition of proinflammatory molecules via antagonist monoclonal antibodies has improved clinical outcomes, but the complexity of the underlying immune dysregulation results in high variability. Rather than a ‘one size fits all’ treatment approach, an identification of disease endotypes may permit the development of effective therapeutic strategies that address the contributors of disease progression. Here, the authors present a literature review of the cytokine-associated aetiology of acute and chronic cytokine-mediated tissue damage, describe successes and challenges in developing clinical treatments, and highlight advancements in preclinical therapeutic strategies for mitigating pathological cytokine production.
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