The IL-1RI Co-Receptor TILRR ( FREM1  Isoform 2) Controls Aberrant Inflammatory Responses and Development of Vascular Disease

[Display omitted] •The IL-1RI co-receptor, TILRR, is a potent amplifier of IL-1–induced responses.•Blocking TILRR inhibits IL-1 receptor function and activation of inflammatory genes.•TILRR expression is high in atherosclerotic lesions but low in healthy tissue, allowing distinct inhibition at sites of inflammation.•Genetic deletion of TILRR and antibody blocking of TILRR function reduce plaque development and progression of atherosclerosis. Lesions exhibit low levels of macrophages and increased levels of smooth muscle cells and collagen, characteristics of stable plaques. Expression of the interleukin-1 receptor type I (IL-1RI) co-receptor Toll-like and interleukin-1 receptor regulator (TILRR) is significantly increased in blood monocytes following myocardial infarction and in the atherosclerotic plaque, whereas levels in healthy tissue are low. TILRR association with IL-1RI at these sites causes aberrant activation of inflammatory genes, which underlie progression of cardiovascular disease. The authors show that genetic deletion of TILRR or antibody blocking of TILRR function reduces development of atherosclerotic plaques. Lesions exhibit decreased levels of monocytes, with increases in collagen and smooth muscle cells, characteristic features of stable plaques. The results suggest that TILRR may constitute a rational target for site- and signal-specific inhibition of vascular disease.