IL-1RAP, a Key Therapeutic Target in Cancer.

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

The family of the interleukin-1 receptors.

The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

DIGIRR as a member of the toll/IL-1R family negative regulates NF-κB signaling pathway in miiuy croaker.

The double-Ig-IL-1R related molecule (DIGIRR) is a member of the TIR (Toll -Interleukin-1 receptor) superfamily and plays an important role in the immune system, it is also as a negative regulator of the IL-1 signaling pathway. In this study, we identified and characterized the miiuy croaker DIGIRR (mmi-DIGIRR) gene. The results of gene structure analysis indicated that there were differences between the mmi-DIGIRR and mammalian SIGIRR, which there were two immunoglobulin (Ig) domains contained in extracellular region of mmi-DIGIRR. Sequence alignment analysis showed that fish DIGIRR shared some conserved sequences with other vertebrates and the evolution was relatively conservative. In order to further validate the function of mmi-DIGIRR and its expression levels in various tissues of fish, qRT-PCR has been conducted. The results showed DIGIRR has significant expression levels in liver, skin and muscle while expression levels in heart are low. The LPS-induced NF-κB activation was inhibited by overexpression of DIGIRR significantly. In conclusion, the evolution and function of mmi-DIGIRR were comprehensively analyzed in this study, which would provide a theoretical basis for the future research of fish DIGIRR.

The interleukin-1 receptor family.

The activity of each member of the IL-1 family of ligands is mediated by its own receptor. Each ligand binds specifically to the extracellular "ligand binding chain" containing three Ig-like regions. With the exception of the IL-1 and IL-36 receptor antagonists, a second chain, termed the "accessory chain", is recruited, forms a heterotrimetic complex with the ligand binding chain and the ligand, and signal transduction is initiated. Each ligand binding or accessory chain shares a common cytosolic segment termed the Toll-IL-1-receptor (TIR) domain. Another family of 13 receptors, termed Toll-like receptors (TLR), have extracellular leucine-rich repeat domains, which bind a broad spectrum of microbial products. All TLR share a nearly identical TIR domain with all members of the IL-1 receptor family. Hence signal transduction and the biological consequences of TLR ligands and IL-1 family ligands are often the same and both receptor families contribute to innate inflammation and host defense. The IL-1 family of receptors is comprised of ten distinct but related gene products. The receptors are indicated by the term IL-1 receptor (IL-1R) followed by a numeral, assigned chronologically by discovery, for example, IL-1R1, IL-1R2, IL-1R3, etc. The ligand binding chain for IL-1α and IL-1ß is IL-1R1 and the accessory chain is IL-1R3. IL-1α, IL-1ß, IL-33 and IL-36 use IL-1R3 as their accessory chain. IL-1R2 is a non-signalling "decoy" receptor that sequesters the IL-1ß and IL-1R3. IL-1R8 exhibits anti-inflammatory properties by reducing IL-1 and TLR signalling. Presently there are two orphan receptors, IL-1R9 and IL-1R10, which have no known function. This review examines the characteristics and functional roles of the IL-1R family in the regulation of innate inflammation, host defense and acquired immunity.

Differential expression and evolution of three tandem, interleukin-1 receptor-like 1 genes in rainbow trout (Oncorhynchus mykiss).

Interleukin-1 receptor-like 1 (Il1rl1 or ST2), a member of the interleukin-1 receptor family, has pleiotropic roles including tissue homeostasis, inflammation, immune polarization, and disease resistance in mammals. A single orthologue was previously described in salmonid fish; however, a recently improved genome assembly of rainbow trout (Oncorhynchus mykiss) revealed three adjacent, tandem il1rl1 orthologues on chromosome Omy 03. Here, we report the genomic organization and evolution of the three il1rl1 genes (il1rl1α, il1rl1ß, il1rl1γ), and use both RNA-seq and gene-specific qPCR methods to quantify expression patterns. Nucleotide sequence homology between the three genes is >95% and each predicted protein contains three IG/IG-like domains, a transmembrane region and a TIR domain. The amino acid sequence homology of the rainbow trout il1rl1 genes are highly related to two functional copies in Atlantic and Coho salmon (∼94%) but relatively low (22-26%) with avian and mammalian species. Transcript abundance measured by RNA-seq in 15 tissues of healthy adult rainbow trout indicate constitutive expression of each gene. In whole body lysates, il1rl1α was shown to have >20 fold mRNA expression compared to il1rl1ß and il1rl1γ as measured by qPCR assays specific to il1rl1α or il1rl1γ, as well as a multi-gene qPCR assay (il1rl1α,ß,γ). Unrooted phylogenetic trees grouped the rainbow trout il1rl1 genes apart from other interleukin-1 receptor family genes and genomic comparisons identify preserved synteny between mammals, birds and salmonids albeit a pseudogene is present in both Atlantic salmon and Coho salmon. Phylogenetic analyses suggest that the three genes arose by tandem duplication but are inconclusive whether these events occurred prior-to or after salmonid speciation. These findings further the understanding of interleukin receptor family evolution and their contribution to teleost immune function.

Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies.

Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP). We report the discovery and characterization of MAB92, a potent, high affinity anti-human IL-36 receptor antagonistic antibody that blocks human IL-36 ligand (α, ß and γ)-mediated signaling. In vitro treatment with MAB92 directly inhibits human IL-36R-mediated signaling and inflammatory cytokine production in primary human keratinocytes and dermal fibroblasts. MAB92 shows exquisite species specificity toward human IL-36R and does not cross react to murine IL-36R. To enable in vivo pharmacology studies, we developed a mouse cross-reactive antibody, MAB04, which exhibits overlapping binding and pharmacological activity as MAB92. Epitope mapping indicates that MAB92 and MAB04 bind primarily to domain-2 of the human and mouse IL-36R proteins, respectively. Treatment with MAB04 abrogates imiquimod and IL-36-mediated skin inflammation in the mouse, further supporting an important role for IL-36R signaling in epithelial cell-mediated inflammation.