Deep insight into cytokine storm: from pathogenesis to treatment

Summary of Deep Insight into Cytokine Storm: From Pathogenesis to Treatment (Nie et al.)

Abstract Summary: Nie et al. provide a comprehensive review on cytokine storm (CS), a severe systemic inflammatory syndrome characterized by excessive immune cell activation and elevated cytokine levels. This paper highlights key signaling pathways involved, associated immune cells, targeted organ damage, and management strategies for CS in conditions such as fulminant myocarditis, acute respiratory distress syndrome (ARDS), hemophagocytic lymphohistiocytosis (HLH), and cytokine release syndrome (CRS). The review emphasizes multidisciplinary management and explores novel therapeutic approaches targeting the implicated signaling pathways.

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

Key Points:

Cytokine Storm Pathophysiology: CS involves excessive immune cell activation and release of pro-inflammatory cytokines, significantly contributing to organ dysfunction and high mortality rates in various critical conditions.
JAK-STAT Pathway: Crucial for cytokine signaling, the JAK-STAT pathway significantly influences CS through cytokines like IL-6, TNF, and IFN-γ, making it an important therapeutic target in managing severe inflammatory responses.
Toll-Like Receptors (TLRs): Activation of TLRs plays a vital role in immune dysregulation and CS, promoting inflammatory cytokine production through canonical and noncanonical signaling pathways.
Neutrophil Extracellular Traps (NETs): NETs exacerbate inflammatory responses and organ injury by enhancing cytokine release and immune cell activation, particularly notable in severe infections and autoimmune conditions.
NLRP3 Inflammasome: The NLRP3 inflammasome is a major mediator of inflammation in CS, involved in cytokine maturation (IL-1β, IL-18) and inducing pyroptotic cell death, contributing significantly to inflammatory damage.
Immune Cell Roles: Dysregulated activation of immune cells, including macrophages, T cells, neutrophils, NK cells, and eosinophils, amplifies cytokine release and contributes directly to tissue injury and CS severity.
Organ Damage: CS commonly results in significant organ damage including vascular endothelial dysfunction, cardiac injury, pulmonary dysfunction, renal impairment, hepatic and gastrointestinal injury, and central nervous system involvement.
Diagnostic and Prognostic Tools: Various scoring systems like the HScore and MS score, along with cytokine profiling, aid in early detection and prognostic evaluation of CS, facilitating timely intervention.
Therapeutic Strategies: Management strategies encompass multidisciplinary approaches, including cytokine inhibition (IL-1, IL-6, TNF blockers), JAK inhibitors, supportive organ function management, and life support interventions (e.g., ECMO).
Future Directions: Emerging therapeutic options, such as cytokine-targeting antibodies, JAK inhibitors, and advanced immune therapies, offer promising avenues for more effective CS management.

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

Conclusion: The understanding of CS pathogenesis has significantly advanced, underscoring the necessity for tailored, multidisciplinary treatment strategies. Novel therapeutic approaches targeting cytokines and key signaling pathways represent promising solutions for managing severe inflammatory responses and reducing associated morbidity and mortality.

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

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Deep insight into cytokine storm: from pathogenesis to treatment

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