Calming the inflammatory storm in severe COVID-19 infections: Role of biologics- A narrative review

Abstract

The risk of Coronavirus infection continues, and the fear of resurgence indicates the lack of a successful therapeutic strategy. In severe COVID-19 infection, many immune cells and their products are involved, making management difficult. The abundant release of cytokines and chemokines in severe COVID-19 patients leads to profound hyper inflammation and the mobilization of immune cells, triggering the cytokine storm. The complications associated with the cytokine storm include severe respiratory distress, intravascular coagulation, multi-organ failure, and death. The enormous formation of interleukin (IL)-6 and hemopoietic factors such as granulocyte–macrophage colony-stimulating factor (GM-CSF) are implicated in the severity of the infection. Moreover, these inflammatory cytokines and factors signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway causing the activation of cytokine-related genes. The neutralization of these proteins could be of therapeutic help in COVID-19 patients and could mitigate the risk of mortality. IL-6 antagonist, IL-6 receptor antagonists, GM-CSF receptor inhibitors, and JAK-STAT inhibitors are being investigated to prevent intense lung injury in COVID-19 patients and increase the chances of survival. The review focuses the role of IL-6, GM-CSF, and JAK-STAT inhibitors in regulating the immune response in severely affected COVID-19 patients.

Bioinformatics and in-silico findings reveal medical features and pharmacological targets of biochanin A against colorectal cancer and COVID-19

“…In addition, COVID-19 can activate the PI3K-Akt signaling pathway and can play dual anti-inflammatory and carcinogenic roles [ 48 ]. The JAK-STAT signaling pathway that activates cytokines has been suggested as a target for preventing intense lung injury and increasing the chances of survival in COVID-19 patients [ 49 ]. More importantly, a genetic polymorphism study of COVID-19 patients showed the polymorphism locus near the Janus kinase (JAK) TYK2, the key for IFN, interleukin (IL)-12, and IL-23 signaling, and T helper (Th) 1/Th17 cell mediated antiviral immune responses, suggesting the critical role of the JAK-STAT signaling pathway in the development of cytokine storm in COVID-19 [ 28 ].…”

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

“…GM‐CSF activates the JAK2/STAT3/STAT5 signaling pathway by binding to the β‐chain subunit of the GM‐CSF receptor, thereby regulating the massive release of cytokines, such as IL‐1, IL‐6, and TNF‐α from immune cells (such as DCs, monocytes, and macrophages). 129 , 130 In addition, GM‐CSF‐R may activate other downstream signals, including the activation of NF‐κB and PI3K‐Akt. 131 Thus, regulation of GM‐CSF and its signaling is an important way to improve inflammation in COVID‐19.…”

Regulation of Tripartite Motif-Containing Proteins on Immune Response and Viral Evasion

“…JAK/STAT is initially activated by binding of cytokines, such as IFNα/β, IFNγ, and IL-6. IFNα/β employs TYK2 and JAK1 to phosphorylate STAT1 and STAT2, IFNγ recruits JAK1 and JAK2 to phosphorylate STAT1, and IL-6 leads to one or both JAK-mediated phosphorylations of STAT3 ( Majoros et al, 2017 ; Banji et al, 2021 ). These activated STAT dimers are then transported to the nucleus and promote the transcription of interferon stimulated genes (ISGs; Raftery and Stevenson, 2017 ).…”