Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

Abstract

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.

Fig. 1

The increasing number of publications searched by the key words ‘cytokine release syndrome’ (a), ‘chimeric antigen receptor T (CAR-T) cell’ (b) or ‘COVID-19’ (c) in PubMed (https://pubmed.ncbi.nlm.nih.gov) in recent decades

Fig. 2

The in vivo kinetics of cell counts and cytokine levels in the serum during the CRS process after CAR-T-cell therapy. Patients were treated with tocilizumab or corticosteroids when CRS reached at grade 3–4

Fig. 3

Cellular mechanisms of CAR-T-cell therapy triggering CRS. IL-6 trans-signaling promoted the expansion and antitumor activity of CAR-T cells via the GP130/STAT3 pathway, while apoptosis and pyroptosis were found in tumor cells after CAR-T-cell therapy; monocytes, endogenous T cells, endothelial cells, and granulocyte were all activated

Fig. 4

Cellular mechanisms of CRS in mild and severe patients with COVID-19. Mild patients have more NK and T cells in the peripheral blood (a), while severe patients are exposed to more COVID-19 and have more interstitial fluid accumulation (b). Neutrophil, C-reactive protein (CRP), ferritin, IL-6, TNF-α, D-dimer, and other cytokine in severe patients with COVID-19 were higher than that in mild patients

Fig. 5

Molecular mechanisms of CRS from TNF/NF-κB, IL-1/NF-κB, IL-6/JAK-STAT, and INF-γ/JAK-STAT pathway

Fig. 6

CRS mouse models. a Severe combined immunodeficiency (SCID)-beige mouse model. b Humanized NSG mouse model. c Mouse-derived CAR-T model