IL-1 Receptor Family Review

All IL-1 receptor family members possess three immunoglobulin (Ig)‐like domains in the extracellular receptor segment, while SIGIRR (single Ig domain-containing IL-1 R-related molecule) and IL‐18BP (IL-1 receptor family subtype), have only one Ig‐like domain.

Apart from IL-1R2, almost all IL-1 receptor family members have an intracellular TIR (Toll-like receptor/IL-1 R signaling) domain. IL‐1R2, although lacking a TIR domain, is considered part of this subgroup due to its high similarity to the IL‐1R1.

Six IL-1 receptor family members (IL-1 R1, IL-1 R2, IL-1 R4, IL-1 R5, IL-1 R6 and IL-1 R7) are located on chromosome 2. IL-1 R3 is located on chromosome 3, IL-1 R8 and IL-1 R9 are located on the X chromosome, and IL-18BP and SIGIRR lies on chromosome 11.

The following will briefly highlight each IL-1 receptor family and also present its key functions.

1. IL-1 receptor complex: IL-1R1, IL-R2 and IL-R3

Type I IL-1 receptor (IL-1R1), is the membrane receptor that binds the IL-1 ligands and is responsible for IL-1-mediated inflammatory activation. The extracellular portion encompasses three Ig-like domains, and is responsible for IL-1 binding. The cytoplasmic portion, of about 200 amino acids in length, is homologous to the cytoplasmic domains of the other members of the TIR superfamily. Indeed, IL-1R1 was the first identified TIR receptor.

The crystal structure of IL-1 bound to IL-1R1 reveals that the first and second Ig-like domains are held in rigid orientation by inter-domain sulphide bonds, whereas the third domain is connected by a flexible tether. IL-1RI wraps around IL-1 such that IL-1 interacts with the receptor between the first and second domains and on the side of the third domain. Upon IL-1 binding, the receptor complex is internalized to the nucleus probably by receptor mediated endocytosis.

Type II IL-1 receptor (IL-1R2), the second binding receptor for IL-1, was identified as having an extracellular domain highly homologous to that of IL-1R1 and being able to bind IL-1 with high affinity, but unable to initiate signalling because of its very short cytoplasmic portion lacking the TIR domain.

The membrane-bound IL-1R2 captures IL-1 at the cell surface, whereas sIL-1R2 binds IL-1 in the microenvironment, both preventing IL-1 binding to IL-1R1 on the cell surface and initiation of cell activation. IL-1R2 thus represents one of the major mechanisms of inhibition of IL-1 activity, and has been defined as decoy receptor.

IL-1R3, a second receptor chain, is necessary for IL-1R signalling. This chain, known as the IL-1R accessory chain (IL-1RAcP), is a homologue of the IL-1R1. IL-1R3 does not directly bind to either IL-1α or IL-1β, but it can bind to the complexes IL-1–IL-1R1 or IL-1–IL-1R2, forming high affinity receptor complexes.

2. IL-33 receptor complex: IL-1R4

IL-1R4, the ligand-binding receptor of IL-33, was identified thirty years ago, long before the identification of IL-33 in 2005, and remained as an orphan receptor until then. Despite its similarity with IL-1R1, IL-1R4 is unable to induce an inflammatory response and to bind to any of the known members of the IL-1 family ligands. IL-1R4 is involved in Th2 anti-inflammatory/allergic effector function and to exert a down-regulating activity on IL-1R1 and MyD88- and Mal-dependent TLR signalling.

3. IL-18 receptor complex: IL-1R5, IL-R7 and IL-18BP

IL-1R5, also known as IL-18R or IL-1Rrp1, is the ligand-binding receptor for IL-1. The receptor complex for IL-18 encopasses two chains, similarly to all other receptor complexes in the family.

Within the entire IL-1 receptor family, IL-1R7, the accessory chain for IL-18, is unique, while in all other receptor complexes the promiscuous accessory chain IL-1R3 is used.

Binding of IL-18 to the IL-1R5 is characterised by relatively low affinity (Kd 20-50nM), which is increased over 100-fold (Kd 0.3nM) after formation of the trimeric complex with the accessory chain IL-1R7, a protein of the IL-1 receptor family originally called AcPL, which mediated signal transduction after complexing with IL-1R5.

IL-18BP is a naturally occurring, secreted protein, with high affinity specific binding to mature IL-18 but unable to bind the IL-18 precursor. Regulation of IL-18 activity relies mainly on a soluble IL-18-binding protein (IL-18BP), which binds IL-18 preventing its interaction with the membrane IL-1R5. With the exception of IL-37, IL-18BP does not bind to other members of the IL-1 family nor to any of several cytokines tested. IL-18BP is not a soluble form of the membrane bound IL-1R5, although it acts as a soluble decoy receptor. The IL-18BP structure presents a single Ig-like domain, which has homologies with the D3 of the IL-1R2 and IL-1R5 chains.

4. IL-36 receptor complex: IL-1R6

IL-1R6 was identified in 1996 as an interleukin-1 receptor related protein of 561 amino acids, and called IL 1Rrp2. IL-1 R6 binds IL-1F9 and activates NF-kappa B, and that such activation was inhibited by IL-36Ra (IL-1F5). Cell activation by IL-36 through IL-1R6 requires, as for other IL- 1R complexes, the recruitment of a signalling accessory chain, the promiscuous IL-1R3, leading to activation of both NFB and MAP kinases.

5. Orphan receptors: IL-1R8, IL-R9 and SIGIRR/TIR8

IL-1R8, also known as IL1RAPL1 and TIGIRR-2, is a 696 amino acid-long protein that has structural and sequence homology with the other molecules of the IL-1 receptor family, except for the unusually long intracytoplasmic portion, a characteristic shared with SIGIRR and IL-1R9.

IL-1R9, also known as IL1RAPL2 and TIGIRR-1, has about 63% amino acid identity with IL-1R8 and is encoded, like IL-1R8, by a very large gene on the X chromosome (IL-1R9 on Xq, IL-1R8 on Xp). Similarly to IL-1R8, IL-1R9 was found unable to bind IL-1-like cytokines, and its intracellular portion could not mediate signalling in chimeric constructs encompassing IL-1R1 extracellular portion and IL-1R9 intracellular portion.

SIGIRR (single Ig domain-containing IL-1 R-related molecule), also known as TIR8, is a fringe member of the IL-1 receptor family and acts as a negative regulator of IL-1 receptor and TLR signaling, which dampens ILR- and TLR-mediated cell activation. SIGIRR is a component of the receptor recognizing human IL-37.

References

1. Dinarello, C. A. (2013). Overview of the interleukin-1 family of ligands and receptors. Semin Immunol, 25(6), 389-393.
2. Subramaniam, S., Stansberg, C., & Cunningham, C. (2004). The interleukin 1 receptor family. Developmental & Comparative Immunology, 28(5), 415-428.
3. Boraschi, D., & Tagliabue, A. (2006). The interleukin‐1 receptor family. Vitamins & Hormones, 74, 229-254.