Regulation of immunity and disease by the IL-1 receptor family members IL-1R2 and IL-1R8

Interleukin-1 and other IL-1 family members are key players in immunity and inflammation. The activation of the IL-1 system is tightly regulated, through ligands with antagonistic or anti-inflammatory activity, or decoy and negative regulatory receptors. IL-1R2 and IL-1R8 (also known as SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling, thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens IL-1 receptor- and Toll Like Receptor-mediated cell activation and is a component of the receptor complex recognizing the anti-inflammatory cytokine IL-37. The deregulated activation of the IL-1 system is the potential cause of detrimental local or systemic inflammatory reactions. Here, we summarize our current understanding of the function of IL-1R2 and IL-1R8, focusing on their role in pathological conditions, ranging from infectious and sterile inflammation, to cancer-related inflammation.