An ancient retrotransposon provides species-specific tuning of IL18 inflammatory signaling [EL4_RNAseq]

Species differ markedly in how they regulate immune responses, yet the molecular basis of this variation remains incompletely understood. Here, we show that an ancient LINE2 retrotransposon introduced an intronic polyadenylation signal into the IL18R1 locus, generating a truncated isoform, IL18R1-Short, that lacks the intracellular signaling domain. Using bulk RNA-seq across nine mammals, we find that although this cis-regulatory element is broadly conserved, robust IL18R1-Short expression is species- and tissue-restricted: bats and mice express it at high levels, particularly in barrier tissues (lung, skin, intestine), whereas most other species, including humans, show absent or limited expression. Single-cell lung profiling further shows that this truncated isoform is enriched in mouse epithelial cells. Known IL18 negative regulators, SIGIRR and IL18BP, also show distinct expression patterns across mouse and human lung cell populations, suggesting that these brakes on IL18 signaling are deployed in context-dependent and non-redundant manner. Functionally, IL18R1-Short dampens IL18-induced NFkB signaling in both human and mouse systems, and knockdown of the mouse ortholog amplifies IL18-driven immune and inflammatory gene expression in mouse T cells. Together, these results identify IL18R1-Short as a TE-derived decoy receptor that attenuates IL18 signaling and show that conservation of a TE-derived cis element does not predict conserved regulatory output. More broadly, these findings establish IL18R1-Short as an example of how TEs can generate alternative immune transcripts with species-specific regulatory consequences, highlighting TE-mediated alternative transcription as an underappreciated source of mammalian immune variation.