Beyond Negative Regulation: IL-1R8 and IL-1R2 as Novel Immune Checkpoints

IL-1 family members and their signaling receptors are key drivers of inflammation in sterile or infectious conditions, as well as polarization of the innate and adaptive immunity. Deregulated or excessive activation of the IL-1 system is associated with detrimental inflammatory reactions. Beside signaling receptors, IL-1-family receptors comprise decoy or negative regulatory receptors, which regulate cell activation mediated by IL-1 family ligands. IL-1-family negative regulatory receptors, which include IL-1R8 and IL-1R2, have peculiar structural features and functions essential to the self-regulation of the IL-1 system. IL-1R8 and IL-1R2 emerge as regulatory molecules whose function is context-dependent, spanning from negative regulation of inflammation in infections or conditions of sterile inflammation and cell damage, including cancer-related inflammation, to skewing of myeloid and lymphoid cells, modulation of anti-tumor immunity, and immune checkpoint activity. This review reports new insights into the physio-pathological roles of these two negative regulatory IL-1 family members, emphasizing their mechanisms of action and potential for innovative therapeutic interventions.