IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines
2022; Nature Portfolio; Volume: 23; Issue: 4 Linguagem: Inglês
10.1038/s41590-022-01160-y
ISSN1529-2916
AutoresSiri Tähtinen, Ann-Jay Tong, Patricia Himmels, Jaehak Oh, Andrés Paler-Martı́nez, Leesun Kim, Sara Wichner, Yoko Oei, Mark J. McCarron, Emily Freund, Zhainib Adel Amir, Cecile C. de la Cruz, Benjamin Haley, Craig Blanchette, Jill Schartner, Weilan Ye, Mahesh Yadav, Uğur Şahin, Lélia Delamarre, Ira Mellman,
Tópico(s)Immune Response and Inflammation
ResumoThe 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.
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