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. 2025 Sep 5;55(9):e70050. doi: 10.1002/eji.70050

Beyond Negative Regulation: IL‐1R8 and IL‐1R2 as Novel Immune Checkpoints

Domenico Supino 1, Roberto Garuti 2, Cecilia Garlanda 1,2,✉
PMCID: PMC12412433  PMID: 40911342

ABSTRACT

IL‐1 family members and their signaling receptors are key drivers of inflammation in sterile or infectious conditions, as well as polarization of the innate and adaptive immunity. Deregulated or excessive activation of the IL‐1 system is associated with detrimental inflammatory reactions. Beside signaling receptors, IL‐1‐family receptors comprise decoy or negative regulatory receptors, which regulate cell activation mediated by IL‐1 family ligands. IL‐1‐family negative regulatory receptors, which include IL‐1R8 and IL‐1R2, have peculiar structural features and functions essential to the self‐regulation of the IL‐1 system. IL‐1R8 and IL‐1R2 emerge as regulatory molecules whose function is context‐dependent, spanning from negative regulation of inflammation in infections or conditions of sterile inflammation and cell damage, including cancer‐related inflammation, to skewing of myeloid and lymphoid cells, modulation of anti‐tumor immunity, and immune checkpoint activity. This review reports new insights into the physio‐pathological roles of these two negative regulatory IL‐1 family members, emphasizing their mechanisms of action and potential for innovative therapeutic interventions.

Keywords: cytokines, inflammation, inhibitory receptors, innate immunity

Self‐regulation of the IL‐1 system mediated by the negative regulatory receptors IL‐1R8 and IL‐1R2 results in tuning of inflammation and metabolic rewiring, as well as lymphoid or myeloid cell immune suppression. IL‐1R8 and IL‐1R2 are emerging as potential therapeutic targets to modulate immunopathology and re‐educate lymphoid or myeloid cells, respectively.

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1. Introduction

IL‐1‐family receptors (ILRs) belong to a phylogenetically conserved “system” that comprises ligands with pro‐ or anti‐inflammatory activity, agonist or antagonist function, as well as signaling receptors and decoy or negative regulatory receptors, which co‐evolved from ancestral vertebrates to mammals [1, 2, 3]. As key drivers of inflammation, IL‐1 family members are pivotal in antimicrobial response, polarization of the innate and adaptive immunity, and orientation of anti‐tumor resistance, positioning them as pharmacological targets in a broad range of human diseases [1, 4, 5]. ILRs show a distinctive biochemical structure consisting of an extracellular portion containing three immunoglobulin (Ig)‐like domains and an intracellular Toll/IL‐1R (TIR) domain shared by Toll‐like‐receptors (TLRs), which transduce the downstream signal by recruiting the adaptor protein MyD88. ILRs with inhibitory properties discussed here, IL‐1R8 and IL‐1R2, show peculiar structural features and functions essential to the self‐regulation of the IL‐1 system [1, 3]. As discussed below, their functional activity complements negative regulation mediated by IL‐1Ra, the IL‐1 receptor antagonist. IL‐1Ra is structurally similar to the agonists IL‐1α and IL‐1β and, by binding IL‐1R1 with high affinity, competes with them in the interaction with the signaling receptor, without recruiting the accessory protein IL‐1R3 (IL‐1RAcP). In addition to being induced and secreted in inflammatory conditions, two intracellular IL‐1Ra isoforms constitute a reservoir of IL‐1Ra, which is released upon cell death [1, 4].

This review reports insights into the physio‐pathological roles of two negative regulatory IL‐1 family members, IL‐1R8 and IL‐1R2, emphasizing their mechanisms of action and potential for innovative therapeutic interventions.

2. IL‐1R8

2.1. Structure, Interactors, and Downstream Pathways

IL‐1R8 is characterized by unique structural features, that is, a single Ig‐like domain in the extracellular region, a TIR domain bearing two aminoacidic substitutions, and an unusually long tail, which are compatible with unconventional signaling and function. IL‐1R8‐mediated negative regulation has been described for IL‐1R, IL‐18R, and IL‐33R‐complexes, as well as TLRs [6, 7, 8, 9, 10]. Upon recruitment to ILR or TLR complexes, IL‐1R8 interferes with the assembly of the TIR domain signalosome, hindering the activation of MyD88‐ and IRAK‐dependent pathways, or blocks the translocation of this complex from the receptor [6, 8, 9]. In addition, the extracellular domain of IL‐1R8 limits the interaction between IL‐1R1 and IL‐1R3 (IL‐1RAcP). Upon recruitment to TLRs, IL‐1R8 also disrupts TRAM homodimerization and interaction with TRIF and TLR4 [6]. Thus, IL‐1R8 negatively regulates ILR‐ and TLR‐dependent activation of the downstream cascade (e.g., NFκB‐, JNK‐, and mTOR‐mediated pathways) and the induction of pro‐inflammatory mediators [7, 11, 12] (Figure 1). In studies on IL‐17‐dependent experimental autoimmune encephalomyelitis, IL‐1R8‐deficiency was associated with enhanced MAPK‐, JNK‐ as well as mTOR‐dependent Th17 differentiation and proliferation, suggesting IL‐1R8 regulates both cell activation and metabolism [11].

FIGURE 1.

FIGURE 1

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IL‐1R8 as an immune checkpoint and anti‐inflammatory molecule. (a) IL‐1R8 acts as an immune checkpoint by regulating IL‐18‐dependent stimulation of NK‐cell‐mediated anti‐viral and anti‐tumor activity. (b) IL‐1R8 acts as co‐receptor for IL‐37, which regulates inflammation and NK or CD8+ T‐cell cytotoxicity. (c) In infections, IL‐1R8 has context‐dependent activities, by tuning anti‐microbial responses or inflammation and immunopathology. (d) IL‐1R8 tunes cancer‐related inflammation in epithelial and B cells.

In addition, IL‐1R8 partners with IL‐1R5 (IL‐18Rα) to form the signaling receptor for the anti‐inflammatory cytokine IL‐37 that leads to PTEN activation, as well as MAPK, NFκB, mTOR, TAK1, and inflammasome inhibition [13, 14] (Figure 1). Although the anti‐inflammatory activity of IL‐37 depends on the interaction with IL‐1R8 in several conditions, the formation of a complex between IL‐37, IL‐1R5, and IL‐1R8 has never been formally proven through structural analysis. Furthermore, these studies imply that IL‐1R8 acts in a dual manner by interfering with the assembly of the TIR domain signalosome upon ILR and TLR activation or by acting as an accessory protein for IL‐37 activity.

IL‐1R8 is constitutively expressed in most tissues, especially in the gut, kidney and liver epithelial cells, as well as in dendritic cells, NK cells, and T lymphocytes [15, 16, 17]. IL‐1R8 transcriptional downregulation is induced by pro‐inflammatory molecules in different cell types, such as intestinal epithelial, myeloid cells, and platelets [16, 17]; however, the molecular mechanisms of IL‐1R8 transcriptional regulation are still poorly characterized. Post‐transcriptional regulation has been described, mediated by peptidase USP13, which prevents IL‐1R8 proteasome degradation [18]. Because of its ubiquitous expression, the functional significance of IL‐1R8‐dependent regulation prominently depends on the specific cellular context and on the immunological mechanisms involved, as discussed below.

2.2. Role of IL‐1R8 in Sterile Inflammation and as Immune Checkpoint in Cancer

Since its discovery, IL‐1R8‐mediated mitigation of inflammation of epithelial tissues, such as intestine and lung was documented [1, 17]. In addition, IL‐1R8 regulates sterile inflammation in experimental models of rheumatoid and psoriatic arthritis, systemic lupus erythematosus, and multiple sclerosis [11, 19, 20, 21]. In specific inflammation‐associated cancer models, IL‐1R8 reduced cancer‐related inflammation and tumor susceptibility. Indeed, constitutive activation of NFκB‐induced pathways and increased expression of cell survival and proliferation genes in IL‐1R8‐deficient gut epithelial cells and colon crypts were associated with susceptibility to colitis‐associated colorectal cancer (CRC) and genetic tumor development and progression [12, 22, 23]. Along the same line, lymphoproliferation and autoimmunity‐associated lymphomagenesis were reported in IL‐1R8‐deficient B cells [24, 25]. In these murine tumor models, IL‐1R8 prevented IL‐1‐ and TLR‐driven signaling and malignant transformation associated with chronic inflammatory diseases (Figure 1).

In contrast with these findings, in NK cells, which express high IL‐1R8 levels, IL‐1R8 acts as an immune checkpoint [15]. IL‐1R8 deficiency enhanced NK‐cell‐mediated immune resistance against hematogenous metastases and liver carcinogenesis unleashing IL‐18‐mediated activation, IFN‐γ production, and degranulation through JNK and mTOR [15]. In human NK cells, siRNA‐mediated IL‐1R8 silencing increased cytokine production (e.g., IFN‐γ, TNF, and CCL3) and cytotoxicity [26] (Figure 1).

In line with biochemical and functional studies [27], the IL‐37/IL‐1R8 axis limited antitumor immunity in IL‐37 transgenic mice by mitigating CD8+ T and dendritic cell activation, thereby facilitating tumor immune evasion and increasing susceptibility to colitis‐associated CRC and chemical skin carcinogenesis [28, 29] (Figure 1). The absence of IL‐37 in mice suggests that this species relies on divergent pathways for the regulation of the IL‐1 system. Therefore, the translational relevance of mouse models to human pathophysiology should be carefully validated. However, IL‐37‐expressing Tregs were found to inhibit human NK cells, and pharmacological blockade of IL‐1R8 counteracted Treg‐mediated immune suppression [30]. In contrast, IL‐37 was shown to induce a metabolic reprograming in myeloid‐derived suppressor cells, dampening their immune suppressive phenotype, thus promoting anti‐tumor activity of T cells in orthotopic and humanized patient‐derived xenograft hepatocellular carcinoma models [31].

Immunotherapy targeting the PD‐1/PD‐L1 axis or CTLA‐4 has shown impressive efficacy in the treatment of different tumor types by unleashing T‐ and NK‐cell responses. In addition, other immune checkpoints, such as LAG3, TIM3, TIGIT, and NKG2A, are promising targets to improve immunotherapy efficacy in patients refractory to anti‐PD‐1/PD‐L1 or anti‐CTLA‐4. Collectively, the studies on the regulatory role of IL‐1R8 in autoimmune diseases and cancer [11, 15, 21, 26, 30] support the hypothesis that it functions as an immune checkpoint of lymphoid cells acting through a distinct intracellular pathway, thus providing a new target for combinatorial immunotherapy.

2.3. IL‐1R8 in Infections

IL‐1‐ and TLR‐mediated activation of innate immunity is fundamental to unleash the antimicrobial response. However, a deregulated innate immune response may lead to hyperinflammation and tissue injury. In line with the dual role of the IL‐1 system in infections, IL‐1R8 deficiency is associated with opposite consequences for the host in infection, depending on the pathogenetic or protective functions of the regulated processes in the model (Figure 1). IL‐1R8 deficiency resulted in uncontrolled IL‐1‐mediated inflammatory response and immunopathology in Mycobacterium tuberculosis, Pseudomonas aeruginosa, Aspergillus fumigatus, and Candida albicans mouse infection models [17, 32]. Conversely, enhanced protection was observed in IL‐1R8‐deficient mice in Escherichia coli and Streptococcus pneumoniae infection models, in which the host benefited from myeloid cell hyperactivation. Further, IL‐1R8 deficiency was associated with more efficient NK‐cell‐dependent control of murine cytomegalovirus (MCMV) infection, as revealed by reduced viral titer in spleen, liver, lung, and brain of newborn mice, and increased IFN‐γ production [15].

3. IL‐1R2

3.1. IL‐1R2 Protein and Mode of Actions

IL‐1R2 is a decoy receptor for IL‐1α and IL‐1β, lacking an intracellular TIR domain. Thus, the IL‐1R2/IL‐1R3 (IL‐1RAcP) receptor complex binds IL‐1 but is unable to signal due to its inability to recruit the TIR‐containing MyD88 required for signalosome assembly. In addition, IL‐1R2 acts as a dominant negative molecule limiting the formation of the functional IL‐1R1/IL‐1R3 complex [3, 33] (Figure 2). A soluble form of IL‐1R2 (sIL‐1R2), mainly generated by shedding mediated by inflammation‐induced proteases, or potentially by alternative splicing, scavenges IL‐1α, IL‐1β, and pro‐IL‐1β, but not IL‐1Ra, and increases the affinity between soluble IL‐1R3 and IL‐1 [3, 34], thus limiting excessive IL‐1‐induced inflammation. By binding pro‐IL‐1β that is released upon cell death, sIL‐1R2 inhibits its extracellular proteolytic activation, thus controlling inflammation associated with tissue damage [3]. In addition, an intracellular form of IL‐1R2 prevents the enzymatic cleavage of pro‐IL‐1α, thus promoting silent necrosis in IL‐1R2‐expressing cell types [35] (Figure 2). IL‐1R2 is highly expressed by myeloid cells (e.g., neutrophils, macrophages, dendritic cells, and microglia) at steady‐state condition. A variety of anti‐inflammatory molecules (e.g., IL‐4, IL‐10, and glucocorticoids) upregulate IL‐1R2 protein levels, whereas pro‐inflammatory mediators (IFN‐γ, LPS and TNF) downregulate it [1, 3], in contrast with IL‐1Ra, which is induced by inflammatory stimuli. In line with this, high levels of myeloid‐derived sIL‐1R2 were reported as a favorable prognostic factor reflecting the activation of an anti‐inflammatory response in selected conditions [17], such as arthritis, in contrast with IL‐1Ra, which was positively correlated with disease severity [36].

FIGURE 2.

FIGURE 2

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Intrinsic and extrinsic mechanisms of regulation by IL‐1R2. (a) In myeloid cells, IL‐1R2 promotes an immunosuppressive phenotype and mitigates IL‐1‐dependent inflammation. (b) In the germinal center (GC), IL‐1R2‐expressing T follicular regulatory (Tfr) cells dampen IL‐1‐driven activation of T follicular helper (Tfh) cells, which trigger the humoral response. Treatment with recombinant IL‐1Ra (Anakinra) abolishes B‐cell hyperproliferation and uneducated production of antibodies.

3.2. IL‐1R2‐Dependent Regulation of Inflammation and Immune Suppression

In sterile inflammation, including necrosis, skin inflammation, and arthritis, IL‐1R2 mitigates inflammation severity [35, 37]. Studies in vivo with IL‐1R2‐deficient mice have demonstrated a major role played by IL‐1R2‐expressing monocytes and macrophages in peritonitis models and neuroinflammation [37, 38], whereas IL‐1R2‐expressing neutrophils tuned fibroblast response to IL‐1 in an arthritis model [39]. Pertaining the lymphoid compartments, single‐cell transcriptomic analysis demonstrated the existence of discrete IL‐1R2‐expressing T‐cell subsets in pathology. For instance, three studies dissected the role of IL‐1R2 in T follicular regulatory (Tfr) cells, their cross‐talk with IL‐1R1‐expressing T follicular helper (Tfh) [40, 41, 42]. Persistent IL‐1α‐driven inflammation and hyperreactive germinal centers (GC) were reported in IL‐1R2 conditional knock‐out mice. IL‐1R2 deficiency in Tfr cells increased B‐cell frequency and antibody production, a phenotype abolished by the in vivo treatment with recombinant IL‐1Ra (Anakinra) [41] (Figure 2).

In contrast to sterile inflammation models in which IL‐1R2 blockade is detrimental, in a triple‐negative breast cancer (TNBC) transplantable model, genetic deficiency and pharmacological inhibition of IL‐1R2 reprogrammed macrophages, reinvigorated CD8+ T‐cell tumoricidal activity and amplified the effects of anti‐PD‐1 immunotherapy. In agreement with results obtained in mice, unfavorable prognosis and poor response to anti‐PD‐L1 were associated with high levels of IL‐1R2 in patients with breast cancer [43].

IL‐1R2 has been detected in intratumoral Tregs within different primary and metastatic human tumors and, with the exception of CRC [44], it has been associated with poor prognosis [45, 46]. Maturation and antigen‐specific activation were considered distinctive features of IL‐1R2‐expressing Treg subsets [45, 46]. Intriguingly, IL1R2 is directly regulated by IRF4, a prognostically relevant transcription factor specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity [46]. Chen et al. suggested that Treg‐dependent inhibition of IL‐1 was sufficient to promote pro‐tumoral carcinoma‐associated fibroblasts (CAFs) polarization [47]. IL‐1R2 deficiency in Tregs was shown to decrease MHC‐II expression in CAFs and increase the response to anti‐PD‐1 in an adenocarcinoma‐transplantable model [47], although MHC‐II downregulation is a hallmark of cancer vulnerability. The function of IL‐1R2 in Tregs is still elusive and whether it is cell autonomous or mediated by the soluble form in the tumor microenvironment needs further investigation.

3.3. IL‐1R2 in Severe Infections and COVID‐19

Similarly to IL‐1R8, the role of IL‐1R2 in infection varies depending on the etiology and pathogenic process involved. Upregulation of IL‐1R2 was observed in mouse monocytes in experimental models of Listeria monocytogenes infection, and it was associated with impaired monocyte effector function [48]. The association between IL‐1R2 and a myeloid immunosuppressive signature was confirmed in patients with bacterial sepsis [49, 50, 51] and SARS‐CoV‐2 infection [52, 53]. In these conditions, sIL‐1R2 levels and IL‐1R2 expression were associated with severity of sepsis and COVID‐19 [50, 51, 52], as well as long‐COVID symptoms [53]. In sepsis patients, the molecular profiling of circulating cells revealed a cluster of monocytes, named MS1, characterized by high expression of IL1R2, low levels of HLA‐DR, and limited TNF production [49]. Emergency myelopoiesis was hypothesized as the primary mechanism leading to the generation of MS1 monocytes, since hematopoietic stem and progenitor cells (HSPCs) upregulate MS1 distinctive genes, including IL1R2, upon stimulation with IL‐6, IL‐10, or plasma from patients with sepsis or COVID‐19 [50]. In addition, IL‐1R2was, which was expressed in a subset of circulating monocytes co‐expressing mature macrophage and immune dysfunction features, correlated with immunological markers, cytokine storm, and clinical parameters (e.g., SOFA score, creatinine, and survival), reflecting the infection severity in hospitalized patients [54]. In sepsis, sIL‐1R2 was correlated with IL‐1Ra, indicating concomitant upregulation of these two IL‐1 system inhibitors (although through different upstream regulators) that act through distinct mechanisms [51]. The treatment with dexamethasone of COVID‐19 patients was associated with the promotion of immunosuppressive neutrophils and upregulation of IL‐1R2, suggesting the modulation of neutrophil‐related inflammatory processes as a mechanism of action for dexamethasone [55].

4. Concluding Remarks

The IL‐1 system includes key mediators of innate and adaptive immunity involved in diverse pathways of microbial recognition and activation, as well as the orientation of lymphoid cell function. Beyond innate immunity to pathogens and immunopathology in classical inflammatory diseases, the IL‐1 system is involved in degenerative diseases, cardiovascular disorders, emergency hematopoiesis, trained innate immunity, and cancer. In particular, IL‐1 is a key component of tumor‐promoting inflammation that affects different cell types of the tumor microenvironment including the recruitment and skewing of tumor‐infiltrating myeloid cells, angiogenesis, and suppression of anti‐tumor immunity [5]. In this picture, IL‐1R8 and IL‐1R2 emerge as regulatory molecules whose function is context dependent, spanning from negative regulation of inflammation, including cancer‐related inflammation, to modulation of anti‐tumor immunity and immune checkpoint activity, underscoring the multifaceted roles and complexity of these negative regulators of the IL‐1 system. As discussed here, their role does not overlap with the regulatory function of IL‐1Ra, the IL‐1 receptor antagonist secreted in inflammatory conditions or released upon cell death. Whereas, IL‐1Ra has been developed as an effective therapeutic molecule in several inflammatory conditions, including sepsis, cytokine release syndrome (CRS), severe COVID‐19, and is currently in several clinical trials [56, 57, 58], targeting IL‐1R8 and IL‐1R2 may reveal more complex, because they have multifaceted impacts on diverse cell populations. For instance, further investigations are needed to exclude unintended lymphocyte activation or inflammation‐driven adverse events in susceptible individuals or cancer‐related inflammation. In addition, since IL‐1R8 and IL‐1R2 are expressed in several cell types, targeting requires selective therapeutic strategies, such as bispecific antibodies or genetic manipulation of cells intended for the adoptive therapy.

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/eji.70050.

Acknowledgments

The study was funded by the Italian Association for Cancer Research AIRC (AIRC 5×1000 project no. 21147 and AIRC IG 30875 to C.G.; Fellowship for Post‐Doc to D.S.), the European Union—Next Generation EU‐PNRR‐MAD‐2022–12375947 and PNC‐E3‐2022‐23683266 PNC‐HLS‐DA to C.G., and the Italian Ministry of University and Research (PRIN‐20174T7NXL and 2022NKEXAT to C.G.). Images provided by Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) and modified.

Open access funding provided by BIBLIOSAN.

Supino D., Garuti R., and Garlanda C., “Beyond Negative Regulation: IL‐1R8 and IL‐1R2 as Novel Immune Checkpoints.” European Journal of Immunology 55, no. 9 (2025): 55, e70050. 10.1002/eji.70050

Funding: The study was funded by the Italian Association for Cancer Research AIRC (AIRC 5×1000 project no. 21147 and AIRC IG 30875), the European Union—Next Generation EU‐PNRR‐MAD‐2022–12375947 and PNC‐E3‐2022‐23683266 PNC‐HLS‐DA, and the Italian Ministry of University and Research (PRIN‐20174T7NXL and 2022NKEXAT).

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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