tetano
Editor, Senior Moderator
Front Immunol
. 2024 Sep 18:15:1444643.
doi: 10.3389/fimmu.2024.1444643. eCollection 2024. SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2
Chao Niu[SUP] 1 2 [/SUP], Tingting Liang[SUP] 1 [/SUP], Yongchong Chen[SUP] 1 [/SUP], Shan Zhu[SUP] 1 3 [/SUP], Lei Zhou[SUP] 1 [/SUP], Naifei Chen[SUP] 1 [/SUP], Lei Qian[SUP] 1 [/SUP], Yufeng Wang[SUP] 1 4 [/SUP], Min Li[SUP] 1 [/SUP], Xin Zhou[SUP] 1 2 4 [/SUP], Jiuwei Cui[SUP] 1 4 [/SUP]
Affiliations
Introduction: Cytokine release syndrome (CRS) is one of the leading causes of mortality in patients with COVID-19 caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague.
Methods: Using spike protein combined with IL-2, IFN-γ, and TNF-α to stimulate human peripheral blood mononuclear cells (PBMCs) to secrete CRS-related cytokines, the content of cytokines in the supernatant was detected, and the effects of NK, T, and monocytes were analyzed.
Results: This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more interleukin-2 (IL-2,) which subsequently cooperates with spike protein to facilitate PBMCs to release IL-1β, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as T cells to release IFN-γ Mechanistically, IFN-γ and TNF-α enhance the transcription of CD40, and the interaction of CD40 and its ligand stabilizes the membrane expression of toll-like receptor 4 (TLR4) that serves as a receptor of spike protein on the surface of monocytes. As a result, there is a constant interaction between spike protein and TLR4, leading to continuous activation of nuclear factor-κ-gene binding (NF-κB). Furthermore, TNF-α also activates NF-κB signaling in monocytes, which further cooperates with IFN-γ and spike protein to modulate NF-κB-dependent transcription of CRS-related inflammatory cytokines.
Discussion: Targeting TNF-α/IFN-γ in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19.
Keywords: CD40; NF-κB; SARS-CoV-2; cytokine release syndrome; monocyte; spike protein.
. 2024 Sep 18:15:1444643.
doi: 10.3389/fimmu.2024.1444643. eCollection 2024. SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2
Chao Niu[SUP] 1 2 [/SUP], Tingting Liang[SUP] 1 [/SUP], Yongchong Chen[SUP] 1 [/SUP], Shan Zhu[SUP] 1 3 [/SUP], Lei Zhou[SUP] 1 [/SUP], Naifei Chen[SUP] 1 [/SUP], Lei Qian[SUP] 1 [/SUP], Yufeng Wang[SUP] 1 4 [/SUP], Min Li[SUP] 1 [/SUP], Xin Zhou[SUP] 1 2 4 [/SUP], Jiuwei Cui[SUP] 1 4 [/SUP]
Affiliations
- PMID: 39359733
- PMCID: PMC11445618
- DOI: 10.3389/fimmu.2024.1444643
Introduction: Cytokine release syndrome (CRS) is one of the leading causes of mortality in patients with COVID-19 caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague.
Methods: Using spike protein combined with IL-2, IFN-γ, and TNF-α to stimulate human peripheral blood mononuclear cells (PBMCs) to secrete CRS-related cytokines, the content of cytokines in the supernatant was detected, and the effects of NK, T, and monocytes were analyzed.
Results: This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more interleukin-2 (IL-2,) which subsequently cooperates with spike protein to facilitate PBMCs to release IL-1β, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as T cells to release IFN-γ Mechanistically, IFN-γ and TNF-α enhance the transcription of CD40, and the interaction of CD40 and its ligand stabilizes the membrane expression of toll-like receptor 4 (TLR4) that serves as a receptor of spike protein on the surface of monocytes. As a result, there is a constant interaction between spike protein and TLR4, leading to continuous activation of nuclear factor-κ-gene binding (NF-κB). Furthermore, TNF-α also activates NF-κB signaling in monocytes, which further cooperates with IFN-γ and spike protein to modulate NF-κB-dependent transcription of CRS-related inflammatory cytokines.
Discussion: Targeting TNF-α/IFN-γ in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19.
Keywords: CD40; NF-κB; SARS-CoV-2; cytokine release syndrome; monocyte; spike protein.