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

Abstract

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.

Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease

“…Macrophages can produce IL-1 in a variety of ways, as detailed above. However, macrophages appear unique in their ability to present IL-1a on the cell surface ( Figure 1C) (76,77). Cell surface (csIL-1a) is induced de-novo after TLR ligation and associates with the membrane via IL-1R2 and a glycosylphosphatidylinositol (GPI)-anchored protein, with trafficking to the membrane specifically inhibited by IFNg (77).…”

“…However, macrophages appear unique in their ability to present IL-1a on the cell surface ( Figure 1C) (76,77). Cell surface (csIL-1a) is induced de-novo after TLR ligation and associates with the membrane via IL-1R2 and a glycosylphosphatidylinositol (GPI)-anchored protein, with trafficking to the membrane specifically inhibited by IFNg (77). Because csIL-1a is the less active pro-form tethered via the N-term (77), it is both activated and released after cleavage, for example by thrombin (36), permitting wider ranging effects.…”

Ejes inflamatorios y alarminas en el intestino delgado en enfermedad celíaca

“…Desde esta ubicación, la pro-IL-1α es capaz de interactuar con el IL-1R presente en células adyacentes, mecanismo conocido como "juxta-parácrino" (Kurt-Jones, Kiely and Unanue, 1985). Aunque se desconoce cómo se regula la localización de la pro-IL-1α en la membrana, se sabe que este proceso depende de glicosilaciones con D-manosa y/o por modificaciones con lípidos (Di Paolo and Shayakhmetov, 2016;Chan et al, 2020).…”

“…Por otro lado, la IL-1R2, también puede ser liberada al medio extracelular desde donde es capaz de bloquear la unión de IL-1α y su receptor (Di Paolo and Shayakhmetov, 2016). No obstante, investigaciones recientes han descubierto que el IL-1R2 sería necesario para la localización en membrana de la pro-IL-1α (Chan et al, 2020). Esto sugiere que el IL-1R2 no solo actuaría como un inhibidor de la actividad de IL-1α sino también como un agente promotor de su localización en membrana.…”

“…Aunque esto podría ser considerado como una inhibición de la bioactividad de IL-1α, estudios recientes sugieren un rol promotor de IL-1R2 en la localización en membrana de esta alarmina. Por lo cual, la de IL-1α podría no está limitada solo a su liberación, sino que también podrían tener un rol en la membrana celular (Chan et al, 2020).…”