IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulat...

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Vydané v:	Nature immunology Ročník 23; číslo 4; s. 532 - 542
Hlavní autori:	Tahtinen, Siri, Tong, Ann-Jay, Himmels, Patricia, Oh, Jaehak, Paler-Martinez, Andres, Kim, Leesun, Wichner, Sara, Oei, Yoko, McCarron, Mark J, Freund, Emily C, Amir, Zhainib Adel, de la Cruz, Cecile C, Haley, Benjamin, Blanchette, Craig, Schartner, Jill M, Ye, Weilan, Yadav, Mahesh, Sahin, Ugur, Delamarre, Lélia, Mellman, Ira
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Nature Publishing Group 01.04.2022
Predmet:	Animals Cancer vaccines COVID-19 Cytokines IL-1β Inflammation Inflammation - immunology Inflammation - metabolism Interleukin 1 Interleukin 1 receptor antagonist Interleukin 1 Receptor Antagonist Protein - genetics Interleukin 1 Receptor Antagonist Protein - immunology Interleukin 1 receptors Interleukin 6 Interleukin-1 - genetics Interleukin-1 - immunology Leukocytes Lipids Mice mRNA vaccines mRNA Vaccines - adverse effects mRNA Vaccines - metabolism Ribonucleic acid RNA Signal transduction Toll-like receptors Vaccines Vaccines, Synthetic
ISSN:	1529-2908, 1529-2916, 1529-2916
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Abstract	The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.
AbstractList	The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling. The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling. The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the ‘interleukin 1 (IL-1)–interleukin 1 receptor antagonist (IL-1ra)’ axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.RNA vaccines have been associated with high reactogenicity. Mellman and colleagues demonstrate that lipid-formulated RNA vaccines trigger IL-1 production and inflammation in humans but this pathway is dampened in mice.
Author	Paler-Martinez, Andres Freund, Emily C Tong, Ann-Jay Oei, Yoko Schartner, Jill M Delamarre, Lélia Himmels, Patricia Ye, Weilan Blanchette, Craig Tahtinen, Siri Oh, Jaehak Kim, Leesun de la Cruz, Cecile C Yadav, Mahesh Sahin, Ugur Mellman, Ira McCarron, Mark J Haley, Benjamin Amir, Zhainib Adel Wichner, Sara
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/35332327$$D View this record in MEDLINE/PubMed
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Snippet	The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not...
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SubjectTerms	Animals Cancer vaccines COVID-19 Cytokines IL-1β Inflammation Inflammation - immunology Inflammation - metabolism Interleukin 1 Interleukin 1 receptor antagonist Interleukin 1 Receptor Antagonist Protein - genetics Interleukin 1 Receptor Antagonist Protein - immunology Interleukin 1 receptors Interleukin 6 Interleukin-1 - genetics Interleukin-1 - immunology Leukocytes Lipids Mice mRNA vaccines mRNA Vaccines - adverse effects mRNA Vaccines - metabolism Ribonucleic acid RNA Signal transduction Toll-like receptors Vaccines Vaccines, Synthetic
Title	IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines
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