Models of Cytokine storm (Sepsis and Covid-19 inflammatory component)

When well-controlled, the innate immune response is the first line of defence of infections. However, excessive responses cause damage to the body. The term “cytokine storm” portraits an immune response out of control. Cytokine storms are associated with various infectious diseases including COVID-19 and sepsis as well as graft-versus-host disease, inflammatory and autoimmune diseases and has also been a consequence of therapeutic interventions. Inflammation associated with a cytokine storm starts locally and then progresses into a systemic response. Even if the term goes way back, there is still a lack of understanding of the molecular mechansims underlying the concept and its contribution to pathogenesis.

Recently, much attention has been given the role of proinflammatory cytokines in pathology during viral infections and the link to disease severity in Acute Respiratory Distress Syndrome (ARDS), one of the major causes of death in COVID-19 patients. ARDS as a consequence of influenza (including avian influenza - H5N1) or corona viruses (Including SARS and MERS CoVs) is characterized by accumulaiton of inflammatory cells, edema formation and marked increase in cytokines. It has been shown that following a viral infection, low levels of antiviral interferons and high levels of proinflammatory cytokines (IL-1b, IL-6, TNFa and chemokines) are produced. This response is accompanied by increased levels of neutrophils and monocytes in blood and tissue. Several proinflammatory cytokines (including IL-6, IL-8, IL-1b), granulocyte-macrophage colony-stimulating factor, reactive oxygen species (ROS) and chemokines contribute to ARDS.

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Cell based acute inflammatory models

In our 3D in vitro model using human whole blood a massive cytokine release is experimentally induced in by activating the same pathways activated by invading pathogens. By culturing the cells in a 3D structure, the cells and soluble inflammatory mediators are allowed to interact in a more physiologically relevant setting. The assay have a fast kinetic and model the acute phase of the cytokine storm. This model can be varied to suit each specific scientific question.

 

(Illustration generated by Redoxis AB using BioRender (2020))

In vivo acute inflammatory models

Administration of the endotoxin Lipopolysaccharide (LPS) or other TLR stimulating agents to mice induce acute inflammatory responses similar to the inflammatory response that occures during the early stages of septic shock and also seen in acute systemic responses in ARDS in COVID-19 patients. Shortly after administration of endotoxin, cytokines and chemokines including TNF-a and IL-6 are released. This model is a fast and cost-effective model for screening of anti-inflammatory properties of test items aimed for treatment of inflammatory and autoimmune conditions. 

A massive cytokine release can be experimentally induced in serval ways. Toxic agents activating Pattern Recognition Receptors (PPRs) such as Toll Like Receptors (TLRs) are often used to model the effect of invading pathogens. LPS is one such toxin that is routinly used to activate a systemic inflammatory resonse. These models have fast kinetics and model the acute phase of the cytokine storm. LPS activates TLR4 and mimics aspects of a bacterial infection. This model is often used as an experimental model for sepsis. 

Resiquimod (R-848) is an agonist to TLR7 and TLR8 and mimics the cytokine response induced by single stranded RNA and viral infections. Cytokine storm can also be induced by superantigens including anti-CD3 and anti-CD28 antibodies. Binding of superagonist antibodies stimulates T cells without antigen-receptor stimulation.  

 

(Illustration generated by Redoxis AB using BioRender (2020))