Potential Pathophysiological Mechanisms Underlying Multiple Organ Dysfunction in Cytokine Release Syndrome

Abstract

In recent decades, many serious respiratory infections have broken out all over the world, including SARS-CoV, MERS, and COVID-19. They are characterized by strong infectivity, rapid disease progression, high mortality, and poor prognosis. Excessive immune system activation results in cytokine hypersecretion, which is an important reason for the aggravation of symptoms, and can spread throughout the body leading to systemic multiple organ dysfunction, namely, cytokine release syndrome (CRS). Although many diseases related to CRS have been identified, the mechanism of CRS is rarely mentioned clearly. This review is intended to clarify the pathogenetic mechanism of CRS in the deterioration of related diseases, describe the important signaling pathways and clinical pathophysiological characteristics of CRS, and provide ideas for further research and development of specific drugs for corresponding targets to treat CRS.

Figure 1

Development of cytokine release syndrome. (a) Antigen presentation: when DAMPs (damage-associated molecular patterns) or PAMPs (pathogen-associated molecular patterns) bind to PRRs (pattern recognition receptors) on the membrane of antigen-presenting cells (APCs) in capillaries, these cells activate immune signal transduction and stimulate immune cells and epithelial cells to release cytokines. (b) Activation of the innate immune system: cytokine secretion results in the recruitment of innate immune cells (e.g., macrophages, neutrophils, and NK cells) in local tissues. (c) Activation of adaptive immune system: innate immune cells further activate adaptive immune cells (T cells and B cells). Immune cells then continue to activate each another, resulting in extensive production of cytokines under the action of positive feedback and causing the formation of a cytokine storm. (d) Cytokine release syndrome: after a cytokine storm is formed, immune cells and the cytokines released by them continue to induce capillary leakage and pyroptosis, which can lead to severe organ structural destruction and functional failure. IP-10: interferon-inducible protein 10; MIP: macrophage inflammatory protein; GM-CSF: granulocyte-macrophage colony-stimulating factor; IL: interleukin; TNF-α: tumor necrosis factor-α; IFN-γ: interferon-γ; NK cells: natural killer cells.

Figure 2

Cytokine signaling pathway activated by IL-6, TNF-α, IFN-γ, IL-1, and the inflammasome. (a) IL-6 mainly mediates signal transduction through Ras-Raf-ERK-MAPK, NF-κB, JAK/STAT3, and PI3K-Akt-mTOR. (b) IFN-γ activates the downstream pathway through JAK/STAT1 and NF-κB to generate a cascade amplification effect. (c) TNF-α promotes inflammatory response diffusion through NF-κB activation (activated by the sequential recruitment of TRAF2, RIP, TAK1, and IKK) and induces apoptosis by activation of AP-1 and caspase-3. After recruitment of TRAF2 and RIP, AP-1 can be activated through three pathways, in which the following key molecules are involved: ① MEKK and JNK, ② P38a, and ③ ERK and MAPK. Caspase-3 levels can be elevated by sequential recruitment of TRADD, FADD, and caspase-8 or via TRADD, ROS, and caspase-9. (d) IL-1 decomposes into IL-1α and IL-1β under inflammasome activation, and then, IL-1β is released through Gasdermin D (GSDMD) lysate pore and induces cell swelling and apoptosis. The first and second signals are necessary for activation of the inflammasome. JAK: Janus kinase; STAT: the signal transducer and activator of transcription; Ras: a GTPase; Raf: Raf kinase; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; SHP2: Src homology 2-containing protein tyrosine phosphatase 2; PI3K: phosphatidylinositol 3 kinase; AKT: protein kinase B (PKB); mTORC1: mammalian target of rapamycin complex 1; TRAF2: TNFR-associated factor 2; RIP: receptor-interacting protein; TAK1: TGF-β-activated kinase 1; TGF-β: transforming growth factor-β; IKK: inhibitor of κB kinase; MEKK: MAP/ERK kinase kinase; JNK: c-Jun N-terminal kinase; p38a: p38 mitogen-activated protein kinase; AP-1: activator protein-1; TRADD: TNFR-associated death domain; FADD: Fas-associated protein with death domain; NLRP3: NOD-like receptor (NLR) protein 3; ASC: adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain; caspase: cysteinyl aspartate specific proteinase.

Figure 3

The mechanism of organ damage in cytokine release syndrome. (a) The mechanism of brain damage in cytokine release syndrome. IL-6 and TNF-α act on the vascular endothelium to increase the permeability of the BBB and activate the astrocytes and microglia to release cytokines, impacting the structure and function of neurons and synapses. (b) The mechanism of lung injury in cytokine release syndrome. Immune cells are recruited to the lungs by IL-6 and activated by cytokines such as TNF and IFN, generating huge amounts of free radicals and proteases, causing pulmonary edema and gas exchange problems. (c) The mechanism of heart damage in cytokine release syndrome. TNF-α and IL-6 can increase oxidative stress, reduce eNOS phosphorylation, and cause coronary endothelial dysfunction. Excessive TNF-α binding to receptors on cardiomyocytes can cause myocardial damage and dysfunction. TNF-α, IL-6, and IL-1 regulate the expression and function of ion channels on myocardial cell membranes, leading to arrhythmia. (d) The mechanism of liver injury in cytokine release syndrome. IL-6 binds IL-6R across the membrane to exert an anti-inflammatory effect. When IL-6 levels rise, it can combine with sIL-6R to promote inflammation and induce the production of acute phase proteins, culminating in microthrombosis and liver amyloidosis. (e) The mechanism of kidney injury in cytokine release syndrome. IL-17 and TNF-α work synergistically to suppress NO production in the vascular endothelium and enhance blood vessel contraction. Due to the chemotaxis of cytokines, T cells are deposited in blood vessels and enter tissues to produce ROS, leading to kidney damage and renal fibrosis. Microthrombi entering the renal capillary network can easily form microinfarction foci, leading to acute necrosis of renal tubules. Abbreviations: BBB: blood–brain barrier; eNOS: endothelial nitric oxide synthase; sIL-6R: soluble IL-6 receptors; NO: nitric oxide.