| First Author | Tahtinen S | Year | 2022 |
| Journal | Nat Immunol | Volume | 23 |
| Issue | 4 | Pages | 532-542 |
| PubMed ID | 35332327 | Mgi Jnum | J:325397 |
| Mgi Id | MGI:7264845 | Doi | 10.1038/s41590-022-01160-y |
| Citation | Tahtinen S, et al. (2022) IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat Immunol 23(4):532-542 |
| abstractText | 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-1beta, 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-1alpha), 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. |
