Cell surface IL‐1α trafficking is specifically inhibited by interferon‐γ, and associates with the membrane via IL‐1R2 and GPI anchors

IL‐1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL‐1α and IL‐1β are translated as proforms that require cleavage for full cytokine activity and release, while IL‐1α is reported to occur as an alternative plasma membrane‐associated form on many cell types. However, the existence of cell surface IL‐1α (csIL‐1α) is contested, how IL‐1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL‐1α after ligation of TLRs. Pro‐IL‐1α tethers to the plasma membrane in part through IL‐1R2 or via association with a glycosylphosphatidylinositol‐anchored protein, and can be cleaved, activated, and released by proteases. csIL‐1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN‐γ, independent of expression level. We also reveal how prior csIL‐1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent‐associated secretory phenotype via csIL‐1α, but rather via soluble IL‐1α. We believe these data are important for determining the local or systemic context in which IL‐1α can contribute to disease and/or physiological processes. TLR ligation induces expression of IL‐1α on the cell surface of macrophages. IL‐1α tethers to the cell surface via IL‐1R2 and a GPI‐anchored protein. IFN‐γ signaling specifically inhibits the trafficking of IL‐1α to the cell surface.