Role of toll‐like receptors in modulation of cytokine storm signaling in SARS‐CoV‐2‐induced COVID‐19

Abstract

Balanced immune regulation is crucial for recognizing an invading pathogen, its killing, and elimination. Toll-like receptors (TLRs) are the key regulators of the innate immune system. It helps in identifying between self and nonself-molecule and eventually eliminates the nonself. Endosomal TLR, mainly TLR3, TLR7, TLR8, and membrane-bound TLR4, has a role in the induction of cytokine storms. TLR7/8 recognizes the ssRNA SARS-COV-2 and when it replicates to dsRNA, it is recognized by TLR3 and drives the TRIF-mediated inflammatory signaling like NF-κB, MAPK.Such signaling leads to significant transcription and translation of pro-inflammatory genes, releasing inflammatory molecules into the systemic circulation, causing an imbalance in the system. So, whenever an imbalance occurs, a surge in the proinflammatory mediators is observed in the blood, including cytokines like interleukin (IL)-2, IL-4, IL-6, IL-1β, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α. IL-6 and IL-1β are one of the driving factors for bringing the cytokine storm into the systemic circulation, which migrates into the other organs, causing multiple organ failures leading to the death of the individual with severe illness.

Artemisia lactiflora Extracts Prevent Inflammatory Responses of Human Macrophages Stimulated with Charcoal Pyrolysis Smoke

“…Prevention and treatment of respiratory tract diseases caused by exposure to air pollution, cigarette smoking, and viral infection are currently interested. 29 , 30 In vitro model mimicking the inflammatory response of alveolar macrophages, the crucial immune cells in response to inhalable toxic substances and viral particles, was selected in this study. We isolated macrophages from blood of healthy donors and differentiated them into macrophages.…”

Immunogenic and reactogenic efficacy of Covaxin and Covishield: a comparative review

“…TLRs are found in macrophages that identify the nucleic acid pattern (ssRNA) of invading viruses. TLR4, TLR7, TLR8, and TLR9 are among these TLRs, but no specific TLRs involved in SARS-COV-2 pathogenesis have yet been identified [ 31 ]. TLRs attach to viruses, which can activate the NF- ĸ B and MAPK signaling pathways, to clean the virus and produce antiviral responses.…”

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

“…Further studies are needed to clarify the involvement of TLR4 as a co-or receptor for SARS-CoV-2. Moreover, TLRs are involved in the activation of the immune response causing a cytokine storm in COVID-19 patients, where TLR-3, -7, -8 through viral RNA recognition triggers the activation of JAK/ STAT, NF-kB, AP-1 signaling pathways resulting in the amplification of pro-inflammatory cytokines (152,153). Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153).…”

“…Moreover, TLRs are involved in the activation of the immune response causing a cytokine storm in COVID-19 patients, where TLR-3, -7, -8 through viral RNA recognition triggers the activation of JAK/ STAT, NF-kB, AP-1 signaling pathways resulting in the amplification of pro-inflammatory cytokines (152,153). Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153). In this sense, HCQ can inhibit endosomal TLR3, -7, -8, and -9 signaling, controlling inflammation in COVID-19 patients and mitigating the detrimental effects of viral infection (152,153).…”

“…Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153). In this sense, HCQ can inhibit endosomal TLR3, -7, -8, and -9 signaling, controlling inflammation in COVID-19 patients and mitigating the detrimental effects of viral infection (152,153).…”