The TIR-domain containing proteins including Interleukin-1 receptors (IL-1Rs), Toll-like receptors (TLRs) and cytoplasmic adaptor proteins such as MAL and MyD88 play a major role in immune signalling. They are vital to innate host defence against infection, inflammation, injury and stress. IL-1R8, also known as single immunoglobulin interleukin-1 receptor-related protein (SIGIRR) is an inhibitory receptor from the IL-1R family which regulates signalling of both IL-1Rs and TLRs. The mechanism of inhibition is not yet known. However, we have identified a potential novel interaction between the TIR domains of human MAL and IL-1R8 using Negative stain-EM and Cryo-EM. This provides new insights into the mechanism behind the inhibition of TLR4 signalling by IL-1R8.