Deep insight into cytokine storm: from pathogenesis to treatment

Abstract

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

Fig. 1

Timeline of insight into cytokine storm. The figure was created with the assistance of Powerpoint

Fig. 2

Cytokine signaling pathways. JAK-STAT pathway: cytokines activate the JAK/STAT pathway and trigger the secretion of a variety of pro-inflammatory mediators. TLRs pathways: Stimulated by the PAMPs or DAMPs, TLRs promote cytokine storm mainly via two signaling pathways: the canonical TLRs-MyD88-MAPK pathway and the noncanonical TLRs-TRIF-IRF3 pathway. The TLRs could also regulate the transcription of NF-κB and cause cytokine production. TCR/BCR/NF-κB pathway: cytokines bind to receptors on immune cells and induces NF-κB pathway activation and induce the activation of multiple cytokines. NLRP3 pathway: the activation of NLRP3 requires two signals: The first signal was the activation of inflammatory transcription factor NF-κB, thereby upregulating pro-IL-1β, pro-IL-18, NLRP3, and caspase-1. The second signaling process was NLRP3 induces the formation of super-molecule signaling inflammasome complex by recruiting ASC, leading to IL-1β maturation and secretion of IL-18, as well as to gasdermin D-mediated pyroptosis. PANoptosome pathway: PANoptosome inflammasome complex was assembled and activated by immune disturbance, promoting caspase-dependent and MLKL-dependent PANoptotosis. Abbreviations: JAK Janus Kinase, STAT signal transducer and activator of transcription, TLRs Toll-like receptors, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, TRIF TIR domain-containing adapter inducing IFN-β, TRAF tumor necrosis factor receptor-associated factor, IRF3 interferon regulatory factor 3, MyD88 myeloid differentiation primary response 88, MAPK mitogen-activated protein kinase, AP-1 activating protein-1, TCR T-cell receptor, BCR B-cell receptor, NF-κB Nuclear Factor kappa B, IκB inhibitor of NF-κB, NLRP3 the NLR family pyrin domain containing 3, NEK7 NIMA-related kinase 7, ASC apoptosis related spot like protein, GSDMD gasdermin D, ZBP1 Z-DNA binding protein 1, AMI2 absent in melanoma 2, MLKL mixed-lineage kinase domain-like pseudokinase. The figure was created with the assistance of FIGDRAW

Fig. 3

Cell death in cytokine storm. Robust release of cytokines has been suggested to correlate with lung injury and multiple organ failure. This state can activate a variety of cell death pathways, including but not limited to PANoptosis, necroptosis, apoptosis, and pyroptosis. Macrophages infected in conditions such as sepsis and HLH can trigger cytokine storm, during which the synergistic stimulation by inflammatory factors TNF and IFN-γ induces PANoptosis in macrophages. Multiple inflammatory cytokines are produced during β-coronavirus infection, HLH, and sepsis. ZBP1, AIM2, and RIPK1 are common triggers of PANoptosome. Cytokines and caspases, including caspase-8, were involved in the immunoregulation stage of sepsis. The coronavirus infection triggered caspase-8-dependent apoptosis and lead to lung damage. SARS-CoV-2-encoded coronavirus products could modulate various key components in the pyroptosis pathways and leading to cytokine storm syndrome. Abbreviations: HLH hemophagocytic lymphohistiocytosis, NK cell natural killer cell, DC dendritic cell, TNFR tumor necrosis factor receptor, ISGs interferon-stimulated genes, IFN interferon, FADD Fas-associated death domain, NLR NOD-like receptor, ASC apoptosis related spot like protein, GSDMD gasdermin D, RIPK receptor interacting protein kinases, MLKL mixed-lineage kinase domain-like pseudokinase, ZBP1 Z-DNA binding protein 1, AMI2 Absent in Melanoma 2, CASP caspase, BCL-2 B-cell lymphoma-2. The figure was created with the assistance of FIGDRAW

Fig. 4

Diagnosis and treatment of fulminant myocarditis. Pathogenesis: pathogens, immune checkpoint inhibitor drugs and allergens activate and recruit immune cells to the myocardium and induce cytokine storm. The cytokine storm threatens cardiac function, causes cardiac contraction disability and arrhythmia, and even multiple organ failure. The symptoms of patients are nonspecific. Diagnosis: the diagnosis of FM includes clinical, pathological and etiological diagnosis. When a patient presents with typical medical history and symptoms, with dramatic progressive circulatory instability or fatal arrhythmia, FM diagnostic procedure should be started. Life support based comprehensive treatment regimen for FM: if a patient is diagnosed with FM, immediate and comprehensive medical care should be initiated. An important aspect of this regimen is the idea of life support. When the patient is suffering circulatory instability, respiratory failure, severe acidosis, mechanical life support such as IABP, ECMO, cardiac pacemaker, ventilation and CRRT should be applied timely. Abbreviations: SBP systolic blood pressure, IABP intra-aortic balloon pump, ECMO extracorporeal membrane oxygenation, SPO2 oxygen saturation, IVIG intravenous immunoglobulin, RR respiratory rate, BiPAP biphasic positive airway pressure. The figure was created with the assistance of Adobe Illustrator

Fig. 5

Viral pneumonia-related cytokine storm. Infection and invasion of viruses trigger local immunity, while the activation of inflammation in infected macrophages and immune cells releases proinflammatory cytokines and interleukins, leading to the cytokine release syndrome in severe viral pneumonia. Abbreviation: TLR Toll-like receptor, JAK Janus kinase, STAT signal transducer and activator of transcription, SARS-CoV severe acute respiratory syndrome-coronavirus, IL interleukin, IFN-γ interferon γ, MERS-CoV Middle East Respiratory Syndrome Coronavirus, TNF tumor necrosis factor, G-CSF granulocyte colony-stimulating factor. The figure was created with the assistance of FIGDRAW

Fig. 6

The treatment system of viral pneumonia. Antiviral drugs should be applied as soon as possible, and the best time to use anti-inflammatory drugs is when the inflammatory response is most obvious. There are also some strategies to monitor and assess diseases: vital signs, kidney injury, ecsomatics and imaging. Abbreviation: CPR cardiopulmonary resuscitation, PCT procalcitonin, ARDS acute respiratory distress syndrome, SIRS systemic inflammatory response syndrome, MOF multiple organ failure, TPE therapeutic plasma exchange. The figure was created with the assistance of FIGDRAW

Fig. 7

Mechanisms and clinical manifestation of HLH-associated CRS. Upon recognition of a target cell, cytolytic T/NK cells polarize preformed, perforin-containing lytic vesicles toward the immunologic synapse, facilitating perforin release to form pores and deliver cytotoxic proteins into the target cell. In primary HLH (pHLH), genetic mutations affecting perforin-mediated cytolysis impair the lytic pathway, resulting in prolonged interactions between cytolytic T/NK cells and target cells. This extended engagement increases the production of inflammatory cytokines (e.g., IFN-γ), leading to hyperactivation of APCs and subsequent hypercytokinemia. In secondary HLH (sHLH), APCs are activated by PAMPs or DAMPs from malignancies and viruses, causing multi-organ dysfunction, including damage to the vascular endothelium, central nervous system, spleen, liver, and bone marrow. Abbreviation: HLH hemophagocytic lymphohistiocytosis, APCs antigen-presenting cells, PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, IFN interferon, TNF tumor necrosis factor, CMV human cytomegalovirus, EBV Epstein-Barr virus. The figure was created with the assistance of Adobe Illustrator

Fig. 8

Mechanisms and clinical manifestations of CAR-T and GVHD-associated CRS. CAR-T: Following infusion, CAR-T cells are transported to the tumor site, where target recognition activates them to proliferate locally and produce cytokines such as IL-6, IFN-γ, GM-CSF, and TNF, along with soluble inflammatory mediators and catecholamines. This activation stimulates various components within the tumor microenvironment, leading to increased cytokine levels in peripheral blood and further expansion of the CAR-T cell population. The resulting cytokine storm can trigger systemic inflammation, potentially leading to multi-organ dysfunction. GVHD: Conditioning chemotherapy or radiation causes tissue damage, releasing pathogen-associated molecular patterns (PAMPs; e.g., LPS) and damage-associated molecular patterns (DAMPs; e.g., from total body irradiation, TBI), which increase the activation of host APCs during the initiation phase. In the donor T cell activation phase, these host APCs activate alloreactive donor CD4⁺ and CD8⁺ T cells. In the effector phase, effector T cells and pro-inflammatory cytokines damage epithelial cells of the skin, gastrointestinal (GI) tract, liver, CNS, kidneys, and lungs, leading to apoptosis and necroptosis, and resulting in the symptoms of aGVHD. Abbreviation: CAR-T chimeric antigen receptor-modified T cells, GM-CSF granulocyte-macrophage colony-stimulating factor, IFN interferon, MIP macrophage inflammatory protein, aGVHD acute graft-versus-host disease, APCs antigen presenting cells. The figure was created with the assistance of Adobe Illustrator

Fig. 9

Future therapeutic targets for drugs and new therapeutic approaches in cytokine storm related diseases. a The important target factors for anti-inflammation therapy. Blood purification using cytokine adsorption columns (b), cytokine nanosponges (c), mesenchymal stem cell (MSC) therapy (d) are the most promising treatments against cytokine storm. Abbreviation: TLR Toll-like receptor, IL interleukin, IFN interferon, TNF tumor necrosis factor, NK natural killer cells, DC dendritic cells, ILC2 the group 2 innate lymphoid cell, Th helper T cells, PGE2 prostaglandin E2, TGF transforming growth factor, MDSC: myeloid-derived suppressor cells, HLA-G5 human leukocyte antigen G5, IDD intervertebral disc degeneration, HGF hepatocyte growth factor, CXCL3 chemokine (C-X-C motif) ligand 3. The figure was created with the assistance of FIGDRAW