An ancient retrotransposon provides species-specific tuning of IL-18 inflammatory signaling

Abstract

Species differ markedly in how they regulate immune responses, yet the molecular basis of this variation remains incompletely understood. Here, we characterize an underexplored regulatory mechanism of the pro-inflammatory IL-18 pathway, centered on a truncated IL18R1 isoform with striking species-specific expression differences. This isoform, IL18R1-Short, derives from an ancient LINE2 retrotransposon insertion that provides an intronic polyadenylation signal, producing a receptor that lacks the intracellular signaling domain. Using RNA sequencing 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 little or no expression. Functionally, IL18R1-Short dampens IL-18-induced NF{kappa}B signaling in human, mouse, and bat systems, and knockdown of the mouse ortholog enhances IL-18-driven immune and inflammatory gene expression in mouse T cells. Together, these results identify IL18R1-Short as a transposable element-derived decoy receptor and highlight alternative transcription as a source of species-specific immune regulation.