IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines
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.
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IL-1Ra also favors the polarization of macrophages towards an immunosuppressive M2 phenotype.
“Previous findings suggest that IL-1Ra also favors the polarization of macrophages towards immunosuppressive M2 phenotype [45]”
From Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris (2024) · cites this paper as [45]
The Discussion (p. 8) says endogenous IL-1ra antagonizes vaccine-induced systemic inflammation, and the results (pp. 6–7) describe its effects on inflammatory responses involving myeloid cells. Neither those passages nor searches for M2 polarization and alternative macrophage activation address whether IL-1ra favors polarization toward an immunosuppressive M2 phenotype. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIL-1 and IL-1Ra are critical regulators of the inflammatory response to mRNA vaccines.
“IL-1 and IL-1Ra have recently been identified a critical regulator of the inflammatory response to mRNA vaccines.51”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [51]
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- Authors
- Tahtinen, S., Tong, A.-J., Himmels, P., Oh, J., Paler-Martinez, A., Kim, L., Wichner, S., Oei, Y., McCarron, M. J., Freund, E. C., Amir, Z. A., de la Cruz, C. C., Haley, B., Blanchette, C., Schartner, J. M., Ye, W., Yadav, M., Sahin, U., Delamarre, L., & Mellman, I.
- Affiliations
- Genentech (US)
- Corresponding author
- Mellman, Ira
- ORCID
- Venue
- Nature Immunology
- Published
- 2022-03-24
- Volume
- 23
- Issue
- 4
- Pages
- 532-542
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W4220967221
- Cited by
- 535
- References
- 52
- Citations by year
- 2026: 100 · 2025: 134 · 2024: 143 · 2023: 116 · 2022: 42
- FWCI
- 42.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- RNA vaccines, interleukin-1, interleukin-1 receptor antagonist, systemic inflammatory response, IL-1β, IL-1α, interleukin-6, lipid nanoparticle formulation, N1-methylpseudouridine, Toll-like receptor signaling, vaccine toxicity, innate immunity
- MeSH terms
- COVID-19, mRNA Vaccines, Animals, Inflammation, Interleukin-1, Lipids, RNA, Vaccines, Synthetic, Mice, Interleukin 1 Receptor Antagonist Protein
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