Alternative titles; symbols
HGNC Approved Gene Symbol: IL1R1
ICD10CM: M86.3, M86.30;
Cytogenetic location: 2q11.2-q12.1 Genomic coordinates (GRCh38): 2:102,070,390-102,179,874 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11.2-q12.1 | ?Chronic recurrent multifocal osteomyelitis 3 | 259680 | Autosomal dominant | 3 |
Interleukin-1, which has a role as a mediator in inflammation, consists of 2 separate but related proteins, IL1-alpha (147720) and IL1-beta (147760). Dower et al. (1986) showed that the cell surface receptors for the 2 forms of interleukin-1 are identical. Sims et al. (1989) cloned the human IL1R gene and compared it with the mouse gene. Both encode proteins containing a single membrane-spanning segment, a large cytoplasmic region, and an extracellular, IL1-binding portion composed of 3 immunoglobulin-like domains. The IL1R gene expressed in human dermal fibroblasts was found to be identical to that expressed in T cells.
Chen et al. (2007) found that the acute neutrophilic inflammatory response to cell injury requires the signaling protein Myd88 (602170). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor-2 (Tlr2; 603028) and Tlr4 (603030) and normal responses in mice lacking Tlr1 (601194), Tlr3 (603029), Tlr6 (605403), Tlr7 (300365), Tlr9 (605474), or Tlr11 (606270) or the IL18 receptor (IL18R; 604494). However, mice lacking IL1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL1-alpha, and IL1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggested that inhibiting the IL1R-MYD88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.
By a combination of somatic cell hybrid analysis and chromosomal in situ hybridization, Copeland et al. (1991) mapped the IL1R gene to human chromosome 2q12. By RFLP analysis in interspecific backcrosses, Copeland et al. (1991) mapped the corresponding mouse gene at the centromeric end of chromosome 1, a region homologous to a portion of human chromosome 2.
Dale and Nicklin (1999) showed by radiation hybrid mapping that IL1R1, IL1R2 (147811), IL1RL2 (604512), IL1RL1 (601203), and IL18R1 (604494) map to 2q12 and are transcribed in the same direction, with IL1R2 being transcribed towards the cluster.
In a 13-year-old girl with chronic recurrent multifocal osteomyelitis-3 (CRMO3; 259680), Wang et al. (2023) identified a de novo heterozygous missense mutation in the IL1R1 gene (K131E; 147810.0001). The mutation, which was found by whole-exome sequencing of the family, was not present in the gnomAD database. RNA sequencing of patient peripheral mononuclear cells showed increased NFKB (see 164011) and MAPK (see 176948) signaling and increased transcription of genes encoding inflammatory cytokines and chemokines. Further studies showed strong activation of patient myeloid cells, including low-density granulocytes (proinflammatory neutrophils) and monocytes, which was associated with hyperactivation of the NFKB pathway. Mutant IL1R1 was unresponsive to inhibition by its antagonist IL1RN (147679), but was still able to interact with and respond to IL1B (147720) and IL1A (147760). Serum IL1RN levels with elevated in the patient, likely reflecting a compensatory mechanism. The findings indicated that reduced binding affinity of mutant IL1R1 to IL1RN triggered downstream inflammatory signaling in a constitutive manner. Studies in mice suggested that the disorder may involve activation of osteoclast-mediated bone resorption (see ANIMAL MODEL).
Using microcomputed tomography, Bajayo et al. (2005) found that mice lacking Il1r1 had decreased trabecular thickness and number, as well as decreased skeletal growth. Transgenic mice overexpressing Il1 receptor antagonist (IL1RA, or IL1RN; 147679) in the central nervous system also had low bone mass, suggesting that silencing of central Il1r1 signaling leads to progressive impairment of accrual and maintenance of bone mass. Both mouse models exhibited increased bone resorption, and the Il1ra-transgenic mice also showed an increase in bone formation, as observed in human osteoporosis. Hormone levels in the mutant mice did not differ from wildtype. Bajayo et al. (2005) concluded that pathways other than the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes communicate the central IL1 signal to bone.
Wang et al. (2023) found that mice with a homozygous R134E mutation in the Il1r1 gene, which is homologous to the human K131E mutation, showed increased expression of proinflammatory cytokines and developed severe collagen antibody-induced arthritis with prominent bone lesions and articular erosion associated with infiltration of inflammatory cells and increased osteoclast formation. Treatment with a modified IL1 trap with the mutation resulted in a stronger antiinflammatory effect in vitro compared to the wildtype IL1 trap. The findings supported a central role of dysregulated IL1 signaling in the development of osteomyelitis and arthritis.
In a 13-year-old girl with chronic recurrent multifocal osteomyelitis-3 (CRMO3; 259680), Wang et al. (2023) identified a de novo heterozygous c.391A-G transition in the IL1R1 gene, resulting in a lys131-to-glu (K131E) substitution in the second extracellular immunoglobulin-like domain. The mutation, which was found by whole-exome sequencing of the family, was not present in the gnomAD database. In vitro studies showed that the mutation impaired the interaction between IL1R1 and its antagonist IL1RN (147679), but not with IL1A (147760) or IL1B (147720). The findings indicated that reduced binding affinity of mutant IL1R1 to IL1RN triggered downstream inflammatory signaling in a constitutive manner.
Bajayo, A., Goshen, I., Feldman, S., Csernus, V., Iverfeldt, K., Shohami, E., Yirmiya, R., Bab, I. Central IL-1 receptor signaling regulates bone growth and mass. Proc. Nat. Acad. Sci. 102: 12956-12961, 2005. [PubMed: 16126903] [Full Text: https://doi.org/10.1073/pnas.0502562102]
Chen, C.-J., Kono, H., Golenbock, D., Reed, G., Akira, G., Rock, K. L. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13: 851-856, 2007. [PubMed: 17572686] [Full Text: https://doi.org/10.1038/nm1603]
Copeland, N. G., Silan, C. M., Kingsley, D. M., Jenkins, N. A., Cannizzaro, L. A., Croce, C. M., Huebner, K., Sims, J. E. Chromosomal location of murine and human IL-1 receptor genes. Genomics 9: 44-50, 1991. [PubMed: 1672292] [Full Text: https://doi.org/10.1016/0888-7543(91)90219-5]
Dale, M., Nicklin, M. J. Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q. Genomics 57: 177-179, 1999. [PubMed: 10191101] [Full Text: https://doi.org/10.1006/geno.1999.5767]
Dower, S. K., Kronheim, S. R., Hopp, T. P., Cantrell, M., Deeley, M., Gillis, S., Henney, C. S., Urdal, D. L. The cell surface receptors for interleukin-1(alpha) and interleukin-1(beta) are identical. Nature 324: 266-268, 1986. [PubMed: 2946959] [Full Text: https://doi.org/10.1038/324266a0]
Sims, J. E., Acres, R. B., Grubin, C. E., McMahan, C. J., Wignall, J. M., March, C. J., Dower, S. K. Cloning the interleukin 1 receptor from human T cells. Proc. Nat. Acad. Sci. 86: 8946-8950, 1989. [PubMed: 2530587] [Full Text: https://doi.org/10.1073/pnas.86.22.8946]
Wang, Y., Wang, J., Zheng, W., Zhang, J., Wang, J., Jin, T., Tao, P., Wang, Y., Liu, C., Huang, J., Lee, P. Y., Yu, X., Zhou, Q. Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design. Immunity 56: 1485-1501.e7, 2023. [PubMed: 37315560] [Full Text: https://doi.org/10.1016/j.immuni.2023.05.014]