Signaling and inhibition of signaling by IL-1Rs. (A) IL-1α (either precursor or mature) or mature IL-1β bind to the IL-1RI and with the IL-1RAcP forms the receptor heterodimeric complex. The TIR domain of each receptor chain approximate recruit MyD88, followed by phosphorylation of IL-1R–associated kinases (IRAKs) and inhibitor of NFκB kinase β (IKKβ), resulting in a signal to the nucleus. (B) In the brain and spinal cord, the variant IL-1RAcPb can form the heterodimeric complex with IL-1α or IL-1β and IL-1RI, but this complex fails to recruit MyD88, and there is inhibition of the IL-1 signal. The failure to recruit MyD88 may be because of an altered TIR domain (indicated as TIRb). (C) IL-1Ra binds to IL-1RI, but there is no signal because there is failure to form a complex with IL-1RAcP. (D) IL-1β binds to the IL-1RII, but lacking a cytoplasmic segment, there is no signal. (E) Because of an altered TIR domain (indicated as TIRb), SIGIRR inhibits IL-1 and TLR signaling. SIGIRR can form a complex with IL-33 (not shown) and inhibit IL-33 signaling. (F) IL-1Rrp2 binds IL-36α, IL-36β, or IL-36γ and forms a complex with IL-1RAcP. The TIR domain of each receptor chain approximates and recruits MyD88 similar to that shown in panel A. (G) IL-36Ra binds to IL-1Rrp2 but fails to form a complex with IL-1RAcP. Thus, IL-36Ra prevents the binding of IL-36α, IL-36β, or IL-36γ to IL-1Rrp2, and IL-36Ra is the natural receptor antagonist IL-36.