Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions

Abstract

The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID-19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS-CoV-2 is important in providing otential therapeutic targets and treatment strategies against COVID-19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID-19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID-19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID-19.

Keywords: COVID‐19; cytokine storm; immunopathology; immunotherapy; inflammatory pathways.

FIGURE 1

Entry of SARS‐CoV‐2 and pathogenesis of COVID‐19. SARS‐CoV‐2 enters the host and its S protein interacts with ACE2 and is initiated by TMPRSS2, which promotes endocytosis to infect respiratory epithelial cells and immune cells. During infection, rapid viral replication triggers PAMP and DAMP, causing a strong immune response and immune dysregulation. Immune cells are extensively activated and secrete large amounts of inflammatory factors, causing excessive inflammation and cytokine storm, which can lead to immunopathological impairment of COVID‐19, closely related to the severity of the disease. The clinical presentation of COVID‐19 patient progresses from mild or moderate symptoms (fever, cough, myalgia, and pneumonia) to severe or critical symptoms (MAS, HLH, ARDS, DIC, and multiorgan failure) and eventually to death. The figure is drawn by BioRender software. Abbreviations: ACE2, angiotensin‐converting enzyme 2; ARDS, acute respiratory distress syndrome; DAMP, danger‐associated molecular pattern; DIC, disseminated intravascular coagulation; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; PAMP, pathogen‐associated molecular pattern; TMPRSS2, transmembrane serine protease 2

FIGURE 2

Toll‐like receptor signaling pathway in COVID‐19. TLR2/6 and TLR4 are located on the cell membrane, while TLR3, TLR7/8, and TLR9 are located on the endosome surface. TLRs recognize invading pathogens by sensing PAMP and activate the regulation of host innate immunity and cytokines. TLR activation leads to the production of proinflammatory cytokines and I IFN through its major downstream proteins MYS88 and TRIF. The S protein of SARS‐CoV‐2 activates TLR2 and TLR4; TLR3 senses intracellular viral dsRNA; TLR7/8 recognizes viral ssRNA; and TLR9 senses mtDNA damage caused by viral infection. Activated TLR regulates the production of proinflammatory factors through a series of signaling in the NF‐κB pathway and activates IRF3/7 to produce I IFN. The figure is drawn by BioRender software. Abbreviations: dsRNA, double‐strand RNA; I IFN, type 1 interferon; IRAK4, interleukin‐1 receptor‐associated kinase 4; mtDNA, mitochondrial DNA; MYD88, myeloid differentiation primary response 88; NF‐κB, nuclear factor‐kappaB; ssRNA, single‐strand RNA; TRAF, tumor necrosis factor receptor‐associated factor; TRIF, TIR‐domain‐containing adapter‐inducing interferon‐β

FIGURE 3

JAK/STAT pathway in COVID‐19. JAK transmits extracellular signals for many inflammatory factors (IL‐2, IL‐4, IL‐6, IL‐7, TNF‐α, IL‐10, GM‐CSF, and IFN), JAK phosphorylates and subsequently activates STAT dimers, which translocate the signals into the nucleus. These inflammatory factors promote inflammation, cytokine storm, and COVID‐19 pathogenesis through the JAK/STAT pathway. The figure is drawn by BioRender software.

FIGURE 4

The NF‐κB pathway and its crosstalk cellular signaling pathway in COVID‐19. Activation of the classical pathway involves mainly stimulation of TNF‐α, IL‐1, and Toll‐like receptor ligands, induces IκBα phosphorylation (catalyzed by IκB kinase [IKK]: IKKα, IKKβ, and NEMO complex), and in turn translocates heterodimers of p65 and p50 into the nucleus. The nonclassical pathway is stimulated mainly by specific TNF family cytokines, and IKKα‐derived p100 phosphorylation (occurs in a RelB‐dependent manner) generates the transcriptionally active p52‐RelB complex, which activates the pathway. The overactivated NF‐κB pathway produces large amounts of proinflammatory cytokines (IL‐1, IL‐2, IL‐6, IL‐8, IL‐12, TNF‐α, and GM‐CSF) and chemokines (CCL2, CXCL10, and CXCL9). This is an important pathogenic mechanism leading to COVID‐19 inflammation and cytokine storm. In addition, JAK/STAT pathway, Ang II accumulation, p38 MAPK pathway, endoplasmic reticulum stress, and STING also crosstalk with NF‐κB pathway. The figure is drawn by BioRender software.

FIGURE 5

Potential therapeutic drugs targeting COVID‐19. Multiple inhibitors or drugs that have been used or are being considered clinically for the treatment of COVID‐19 include interventional therapies that target individual proinflammatory cytokines or their receptors and associated inflammatory pathways. The figure is drawn by BioRender software. Abbreviations: colchicine, CQ/HCQ, chloroquine/hydroxychloroquine; DHZ, hydrogen ginger oleone; EAS, extraction of Asparagus officinalis stem; NSAIDs, nonsteroidal anti‐inflammatory drugs