Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease

Abstract

Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.

Keywords: inflammation; innate immunity; interleukin 1; negative regulation; toll-like-receptors.

Figure 1

Negative regulation of IL-1-mediated pathways by IL-1R2. IL-1R2 differs from the other ILRs for the absence of the characteristic intracellular TIR domain, thus being incapable of signaling. IL-1R2 influences several mechanisms involved in the IL-1-mediated signaling cascade. IL-1R2 interacts with IL-1R3, acting as a dominant negative and impeding the formation of the IL-1R1//IL-1R3 signaling receptor complex; then, IL-1R2//IL-1R3 prevents the interaction between the ligands and the IL-1R1//IL-1R3 complex, by competitive binding to the pro-inflammatory cytokines IL-1α and IL-1β, thus acting as a decoy for the ligands. In addition, sIL-1R2 acts as a soluble decoy by binding IL-1α and IL-1β, as well as pro-IL-1β, blocking its enzymatic cleavage by caspase-1. The interaction of sIL-1R2 with the soluble form of IL-1R3 further increases the affinity for the ligands. Finally, in cytosol soluble form, IL-1R2 regulates the pro-inflammatory activity of IL-1α by preventing the enzymatic cleavage of pro-IL-1α, acting as an intracellular decoy.

Figure 2

Roles of IL-1R2 in pathology. Experimental animal models, in vitro and ex vivo experiments, as well as scRNA-sequencing and transcriptomic analysis demonstrated the role of IL-1R2 as a key modulator and as a biomarker of acute and chronic inflammation in several pathological contexts. In particular, IL-1R2 plays a non-redundant role in regulating macrophage polarization, anti-microbial response and infections (such as sepsis and COVID-19), sterile inflammation (such as arthritis, liver, skin and CNS inflammation), neurodegenerative disorders and cancer. Full-length and sIL-1R2 have also been proposed as novel biomarkers for prognosis in infectious diseases, neurodegenerative disorders, rheumatoid arthritis, ulcerative colitis and cancer.

Figure 3

Mechanisms of negative regulation mediated by IL-1R8. IL-1R8 is characterized by a single extracellular Ig domain, a transmembrane domain, an intracellular TIR domain and an unusually long tail of 95 residues. The IL-1R8 TIR domain differs from the TIR domains of other ILRs for the substitution of two conserved residues (Ser447 and Tyr536 with Cys222 and Leu305), suggesting unconventional signaling. IL-1R8 inhibits the signalling pathways downstream ILRs and TLRs by competing with the recruitment of MyD88 and IRAK at the TIR domain, thus dampening the signaling pathways involved in NF-κB and JNK activation. In addition, in T, NK and epithelial cells, IL-1R8 negatively regulates the activation of the mTOR pathway. IL-1R8, together with IL-1R5, is part of the signaling receptor of the anti-inflammatory molecule IL-37. The IL-37//IL-1R5//IL-1R8 tripartite complex inhibits MAPK, NF-κB, mTOR, TAK1 and Fyn, and activates STAT3, Mer, PTEN and p62(dok) signalling, thus leading to an anti-inflammatory pathway.

Figure 4

Roles of IL-1R8 in pathology. IL-1R8 fine tunes innate and adaptive immune responses in different pathological conditions, thus acting as a key modulator of inflammation. IL-1R8 plays a non-redundant role in bacterial and fungal infections, allergy, autoimmune diseases, renal inflammation, thrombosis, neuro-inflammation and neuronal plasticity, intestinal inflammation, and cancer (colorectal cancer, breast cancer, prostate cancer and CLL). Recently, IL-1R8 has emerged as a novel checkpoint molecule in NK cells. In particular, IL-1R8 modulates maturation and activation of murine and human NK cells, thus regulating their antiviral and antitumor potential. In infections, IL-1R8 plays a dual role: in green, the conditions in which IL-1R8 has a protective role by preventing immunopathology; in red, the specific infections in which by negatively tuning innate responses, IL-1R8 prevents the development of effective anti-microbial resistance. Similarly, in cancer, IL-1R8 tunes cancer-related inflammation in specific tumors (in green), or acts as a checkpoint for NK cells, restraining their anti-tumor and anti-metastatic (and anti-viral) potential.