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. 2021 Mar 30;333:511–520. doi: 10.1016/j.jconrel.2021.03.043

Fig. 4.

Fig. 4

Proposed innate immune signaling in response to mRNA vaccination. The internalization of mRNA LNPs can be detected by innate immune sensors that are localized in the endosomes and cytosol. The detection of mRNA, by the endosomal TLR/8, recruits the MYD88 signal transduction adaptor and leads to the expression of type I IFNs (IFN-α and IFN-β) through IFN regulatory factor 7, and to the secretion of other proinflammatory cytokines through nuclear factor κB (NF-κB). In addition, dsRNA contaminants and/or secondary structures in the mRNA product can interact with TLR3 in the endosomes, recruiting TRIF, as well as upon their arrival in the cytosol be detected by RIG-I and MDA5, binding MAVS. The activation of TRIF and MAVS is followed by molecular cascades that results in the expression of type I IFNs in control of IRF3 and IRF7. In turn, the type I IFN cytokines bind autocrine or paracrine receptors, which eventually regulates the gene expression of hundreds of proteins involved in antiviral immunity. This includes the expression of MHC-I and co-stimulatory molecules, needed for T cell responses, as well as antiviral proteins involved with undesirable anti-RNA responses. Methods such as the introduction of modified nucleotides, the removal of dsRNA fragments, and sequence-engineering, can be utilized to minimize or control the type I IFN activity of mRNA. However, it remains unclear how to strike the perfect balance between obtaining sufficient mRNA-encoded antigen expression and adequate immunostimulation in order to support adaptive immunity. In addition, more research is needed to investigate whether and how the recognition of lipid components in the LNP vehicle might contribute to the innate immune response to mRNA vaccines. Abbreviations: IRF; interferon regulatory factor, ISG; interferon-stimulated gene, NF-κB; nuclear factor-κB, MAVS; mitochondrial antiviral signaling protein, MDA5; melanoma differentiation-associated protein 5, MYD88; myeloid differentiation primary response protein 88, TRIF, Toll-IL-1 receptor domain-containing adapter protein inducing IFNβ.