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.

A retrospective study of Pupingqinghua prescription versus Lianhuaqingwen in Chinese participants infected with SARS-CoV-2 Omicron variants

“…Evidence from a wide range of sources suggests that SARS-CoV-2 infection induces an excessive inflammatory response and cytokine storm (CS), and CS is a vital factor in the conversion of patients with COVID-19 from mild to severe and critical illness (Gu et al, 2022). After infection with SARS-COV-2, the innate immune system is triggered, and various inflammatory pathways are activated, among which NLRP/IL-1β, JAK/STAT, TNF-α/NF-κB, and other pathways have been confirmed to be closely related to SARS-CoV-2 infection (Jiang et al, 2020). The levels of various proinflammatory cytokines (interleukin [IL]-6, IL-1β, IL-2R, IL-8, tumor necrosis factor-α [TNF-α], and interferon [IFN]-γ) and immune cells (monocytes, macrophages, neutrophils, dendritic cells, NK cells, CD4 + , and CD8 + T cells) are elevated, resulting in excessive activation of the immune system and occurrence of Frontiers in Pharmacology frontiersin.org inflammatory CS.…”

The syndromic triad of COVID-19, type 2 diabetes, and malnutrition

“…The immunopathogenesis of COVID-19 also involves an excessive inflammatory response that can intensify into a cytokine storm in extreme cases ( 50 , 51 ). Numerous inflammatory pathways are activated in this process, including facilitation of immune cell (e.g., monocytes, macrophages, neutrophils, natural killer cells, and T cells) as well as stimulation and secretion of proinflammatory cytokines (e.g., interferons, interleukins, tumor necrosis factors, and chemokines [e.g., C-base sequence chemokine ligands]) ( 51 ). In turn, a proinflammatory response recruits and activates more innate and adaptive immune cells that overstimulate the immune system, leading to massive inflammation ( 51 ).…”

“…Numerous inflammatory pathways are activated in this process, including facilitation of immune cell (e.g., monocytes, macrophages, neutrophils, natural killer cells, and T cells) as well as stimulation and secretion of proinflammatory cytokines (e.g., interferons, interleukins, tumor necrosis factors, and chemokines [e.g., C-base sequence chemokine ligands]) ( 51 ). In turn, a proinflammatory response recruits and activates more innate and adaptive immune cells that overstimulate the immune system, leading to massive inflammation ( 51 ). This detrimental inflammatory process can incite and exacerbate acute respiratory distress syndrome (ARDS), the leading cause of COVID-19 related mortality.…”

Diagnostic, Prognostic and Mechanistic Biomarkers of COVID-19 Identified by Mass Spectrometric Metabolomics

“…Of note, variations in the systemic metabolite profile provide a close-to-holistic view of complex adaptive responses and may pinpoint valuable biomarkers of COVID-19. Extensive data support the contribution of metabolic perturbations to the immune-inflammatory alterations that characterize disease progression in COVID-19 [ 29 , 30 , 31 ]. However, MS-metabolomics generates large datasets on several hundreds to thousand metabolites that are difficult to interpret in statistical terms [ 11 , 32 ].…”